2-Substituted-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles

ABSTRACT

2-Substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of the formula (I): ##STR1## and the pharmaceutically-acceptable salts thereof, wherein the hydrogen atoms in the 4a position and 9b positions are in a trans relationship to each other and the 5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole moiety is dextrorotatory; X 1  and Y 1  are the same or different and are each hydrogen or fluoro; Z 1  is hydrogen, fluoro or methoxy; M is a member selected from the group consisting of ##STR2## a mixture thereof and C=0 and n is 3 or 4; their use as tranquilizing agents, pharmaceutical compositions containing them and a process for their production.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 5,698, filed Jan.23, 1979, which in turn is a continuation-in-part of application Ser.No. 799,392 filed May 23, 1977, and now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certaintrans-2-substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolederivatives, their use as tranquilizing agents, pharmaceuticalcompositions thereof, a process and intermediates for their production.

2. Description of the Prior Art

Following the introduction of reserpine and chlorpromazine inpsychotherapeutic medicine in the early 1950's, great effort has beenexpended in the search for other tranquilizing agents having improvedbiological profiles, several of which are γ-carboline derivatives, alsoknown in the art as derivatives of pyrido[4,3-b]indole.

In U.S. Pat. No. 3,687,9618-fluoro-2-[3-(4-fluorophenylanilino)propyl]-1,2,3,4-tetrahydro-γ-carbolinewas disclosed as a useful tranquilizer for warm-blooded animals. In U.S.Pat. No. 3,755,584 structurally related compounds with fluorine in the6- or 8-positions and a specific p-substituted phenylalkyl moiety at the2-position were found to have similar activity.

U.S. Pat. No. 3,983,239 discloses hexahydro-γ-carbolines of the formula##STR3## where R¹ is methyl or ethyl and R² is hydrogen, methyl orethyl. The stereochemical relationship of the hydrogen atoms attached tothe carbon atoms at the 4a and 9b positions is not mentioned in thisreference. However, one would expect them to be in a cis relationshipbased on the method of formation of the hexahydro-γ-carboline nucleusfrom a 1,2,3,4-tetrahydro-γ-carboline precursor by catalytichydrogenation in the presence of platinum, a method well known in theart to introduce hydrogen atoms in a cis-configuration to acarbon-carbon double bond. The compounds claimed are neuroleptic agentssaid to be useful in the treatment of schizophrenia.

U.S. Pat. No. 3,991,199 discloses hexahydropyrimido[4,3-b]indoles,useful as analgesics and sedatives, some of which are of interest astranquilizers, some as mucle relaxants and many of them show hypotensiveactivity; the compounds disclosed are of the formula ##STR4## and theirpharmaceutically suitable salts, where the hydrogens attached to thecarbon atoms in the 4a and 9b positions are in trans relationship toeach other and where: when Y^(a) is --H, --Cl, --Br, --CH₃, -tert-C₄ H₉or --OCH₃ ; and when Y^(a) is --CF₃, X^(a) is --H; and R^(a) is, interalia, hydrogen, benzyl; benzyl ring-substituted with methyl, methoxy orchloro; phenethyl; 3-phenylpropyl; 3-phenylpropyl ring-subsituted withchloro, bromo or methoxy.

Recently issued Belgian Pat. No. 845,368 (Derwent No. 00043Y) discloses5-phenyl-hexahydro-β-carbolines, optionally substituted at positions 2and 4 by methyl or ethyl and at position 3 by alkyl having from 1 to 3carbon atoms, allyl or propargyl. They are said to be useful asantidepressants.

Recent West German Offenlegungsschrift 2,631,836, Derwent No. 09738Y,discloses structurally relatedoctahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepines which may bedepicted by the above formula but with an ethylenic bridge between thetwo benzene rings, Y^(a) and X^(a) are hydrogen and R^(a) is --CH₂ CH₂COCH₃ or --CH₂ CH₂ COC₆ H₅. They are said to be useful as analgesics andtranquilizing agents.

U.S. Pat. No. 4,001,263 discloses 5-aryl-1,2,3,4-tetrahydro-γ-carbolinetranquilizers of the formula ##STR5## where X^(b) and Z^(b) may behydrogen or fluoro and values of R^(b) include many of the2-substituents disclosed for the compounds of formula (I). It has now,unexpectedly, been found that thetrans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of the presentinvention have markedly superior tranquilizing activiting when comparedwith the corresponding 1,2,3,4-tetrahydro-γ-carbolines.

SUMMARY

The valuable tranquilizing agents of the present invention are the2-substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles ofthe formula ##STR6## and the pharmaceutically acceptable acid additionsalts thereof, wherein the hydrogens attached to the carbon atoms in the4a and 9b positions are in a trans-relationship to each other and the5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3b]indole moiety isdextrorotatory; X₁ and Y₁ are the same or different and are eachhydrogen or fluoro; Z₁ is hydrogen, fluoro or methoxy; M is a memberselected from the group consisting of ##STR7## a mixture thereof and C=Oand n is 3 or 4.

By the term "5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolemoiety" is meant the moiety of the formula A ##STR8## wherein thehydrogens attached to the carbon atoms in the 4a and 9b positions are ina trans-relationship to each other and X₁ and Y₁ are as defined above.The preferred compounds of the invention are those wherein said moiety(A) is dextrorotatory. The compounds of formula (I) wherein said moiety(A) is levorotatory have been found to be considerably less active astranquilizing agents. Compounds of formula (I) having a mixture of saiddextrotatory and levorotatory moieties, including the racemates, are ofintermediate activity.

The invention further provides methods for the treatment ofschizophrenic manifestations in mammals which comprises orally orparenterally administering to a mammal in need of such treatment atranquilizing amount of a compound selected from those of the formula(I).

Also provided are pharmaceutical compositions active as tranquilizingagents comprising a pharmaceutically acceptable carrier and a compoundselected from those of the formula (I).

The compounds of the present invention have a markedly and unexpectedlysuperior tranquilizing effect over the above mentioned tranquilizingagents of the prior art.

Especially preferred tranquilizing agents of the invention are thefollowing compounds wherein thetrans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole moiety isdextrorotatory, and diastereomers thereof.

trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

trans-5-phenyl-2-[4-hydroxy-4-(p-methoxyphenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-methoxyphenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

trans-5-phenyl-2-(4-hydroxy-4-phenylbutyl)2,3,4,4a,5,9b-hexahydro-1H-pyrido-[4,3-b]indole,

trans-8-fluoro-5-(p-fluorophenyl)-2-(4-hydroxy-4-phenylbutyl)2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

trans-5-phenyl-2-[3-(p-fluorobenzyl)propyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

trans-8-fluoro-5-(p-fluorophenyl)-2-[3-(p-fluorobenzyl)propyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

trans-8-fluoro-5-(o-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido-[4,3-b]indole,

trans-5-phenyl-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

Further valuable compounds of the invention, useful as intermediates arethe dextrorotatory and racemic tricyclic secondary amines of the formula##STR9## and acid addition salts thereof wherein the hydrogens attachedto the carbon atoms in the 4a and 9b positions are in atrans-relationship to each other and one of X₂ and Y₂ is fluoro and theother is hydrogen or fluoro.

Also disclosed is a novel process for producing compounds of formula (I)by reductive alkylation of a tricyclic secondary amine of the formula(VIII) or (XV) with a lactol of the formula ##STR10## wherein Z₁ is asdefined above and q is 1 or 2.

Other novel and valuable compounds of the invention are the enantiomericand racemic 5-aryl-2-hydroxytetrahydrofurans of the formula ##STR11##where Z₁ is as defined above.

DETAILED DESCRIPTION OF THE INVENTION

The tranquilizing agents of the invention are of the formula ##STR12##wherein the hydrogens attached to the 4a and 9b-carbon atoms are in atrans-relationship, the5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]-indole moiety (A) isdextrorotatory and X₁, Y₁, Z₁ n and M are as previously defined. As willbe recognized by one skilled in the art, moiety (A) contains twoassymmetric carbon atoms at the 4a and 9b positions and two resolvedtrans forms (d- and l-) and a racemic form is possible for each valueassigned to X₁ and Y₁. The moiety (A), of course does not exist alone,but may be derived, for example, from the free base of formula (A-H)##STR13## from which the compounds of formula (I) may be derived. Eachof the compounds (AH) exists as a dextrorotatory (d-)enantiomer, alevorotatory (l-)enantiomer and as mixtures of the two including theracemate containing equal amounts of the d- and l-enantiomers. Thedextrorotatory and levorotatory isomers can be distinguished by theirability to rotate the plane of plane-polarized light. The d-form is thatwhich rotates the plane of plane-polarized light to the right and thel-form is that which rotates the plane-polarized light to the left. Aracemic mixture, containing equal amounts of d- and l-enantiomers, doesnot effect the plane of plane-polarized light. For the purposes of thepresent invention, when determining whether a compound is dextrorotatoryor levorotatory, it is the effect of the compound on light having awavelength of 5893 Angstroms (the so-called D line of sodium) which isto be considered. A moiety of formula (A), above, is considered to bedextrorotatory if the hydrochloride salt of the free base of formula(AH) rotates such light to the right.

The following reaction scheme is illustrative of the processes which maybe employed for synthesis of the4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of formula(VIII) wherein X₁ and Y₁ are as previously defined: ##STR14## Apreferred value for R₂ is benzyl for reasons of economy. However, othervalues of R₂ which will also serve in the above scheme will be obviousto those skilled in the art. Examples of such alternate values for R₂are benzyl moieties substituted in the benzene ring by, for example, oneor more members selected from the group consisting of methyl, methoxy,nitro and phenyl; and benzhydryl.

The reduction of the tetrahydro-γ-carbolines of formula (VI) to form the4a,9b-trans-hexahydro compounds of formula (VII) is carried out in anether solvent, usually tetrahydrofuran. In order to assure completereduction a molar excess of borane/tetrahydrofuran complex (BH₃.THF) isordinarily employed and a 100 to 200% molar excess of said complex ispreferred. While the reaction may be carried out at a temperature in therange of about -10° to 80° C., a temperature of from about 0° to 65° C.is preferred. Ordinarily, a solution of the starting material of formula(VI) in tetrahydrofuran is added to an ice-cooled solution of BH₃.THF.After the addition is complete the reaction mixture is heated to refluxand maintained at this temperature for a period of about one to twohours or more. The reaction is ordinarily carried out in the presence ofan inert gas such as nitrogen. When the reaction is substantiallycompleted, the solvent is evaporated and the residue is acidified withan excess of an acid such as, for example, 2 to 12 molar hydrochloricacid. A preferred acidulant is a mixture of equal volumes of acetic acidand 5 molar hydrochloric acid. The acidified mixture is ordinarilyheated at reflux for 1 to 2 hours or more. The desired product may thenbe isolated, for example, by evaporation of any residual ether solventand a portion of the acid mixture and the precipitated product collectedby filtration and washed. In an alternate method of isolation of theproduct (VII), after the reflux period the reaction mixture is filtered,the filtrate cooled and made alkaline by addition of, for example,sodium hydroxide, potassium hydroxide or sodium carbonate. The basicmixture is extracted with a water immiscible organic solvent such as,for example, chloroform, methylene chloride or benzene, the extractsevaporated and the residue purified by silica gel column chromatography,eluting, for example, with ethyl acetate or mixtures of hexane/ethylacetate.

The reduction of tetrahydro-γ-carbolines by BH₃.THF followed by acidtreatment yields hexahydro-γ-carbolines in which the hydrogens attachedto the carbon atoms in the 4a and 9b positions are in atrans-relationship, see, for example, U.S. Pat. No. 3,991,199.

The 2-benzyl compounds of formula (VII) are then converted to thecorresponding 2-hydrogen compounds of formula (VIII). In general, thismay be accomplished by treating the compound of formula (VII) with amolar excess of a lower alkyl chloroformate ester such as, for example,the methyl, ethyl, propyl or isobutyl ester in the presence of asuitable reaction-inert organic solvent, followed by alkalinehydrolysis. Preferred as chloroformate ester is ethyl chloroformatebecause of its ease of availability and efficiency. By a suitablereaction-inert organic solvent is meant one which will substantiallydissolve the reactants under the conditions of the reaction without theformation of byproducts. Examples of such solvents are aromatichydrocarbons such as benzene, toluene and xylene; chlorinatedhydrocarbons such as chloroform and 1,2-dichloroethane, diethyleneglycoldimethylether and dimethylsulfoxide. An especially preferred solvent istoluene.

To the mixture of starting material of formula (VII) in said reactioninert organic solvent is added up to about a ten molar excess of thechloroformate ester. For reasons of economy a molar excess of about 3 to5 is preferable. The resulting mixture is then heated at a temperatureof from about 80°-150° C., typically at the reflux temperature of themixture, for periods of about 6 to 24 hours or more. Ordinarily,refluxing is carried out overnight for reasons of convenience. Thereaction mixture is then evaporated in vacuo and the residue taken up inan alcohol-water mixture, an alkali, for example, sodium hydroxide orpotassium hydroxide, is added in about 10-30 molar excess based on theamount of starting material of formula (VII), and the resulting mixtureheated at reflux, typically overnight. The solvent is then evaporatedand the residue partitioned between water and a water immiscible organicsolvent such as, for example, chloroform, methylene chloride or ethylether and the organic phase evaporated to dryness. The residual productof formula (VIII) may be used as is or further purified by standardmethods known in the art, for example, by column chromatography onsilica gel.

In the case of compounds of the formula (VII) wherein both X and Y arehydrogen and R₂ is benzyl, the corresponding compound of formula (VIII)may be obtained by catalytic debenzylation employing hydrogen andpalladium-on-carbon catalyst. The reaction is typically carried outemploying the hydrochloride salt of the compound (VII) at a temperatureof from about 50° to 100° C., preferably 60°-75° C., and hydrogenpressures of about 20-100 p.s.i. (1.4-7 kg/cm²) in the presence of areaction-inert solvent, for example, methanol, ethanol, isopropanol,ethyl acetate or mixtures thereof with water. When the hydrogen uptakeis complete, the catalyst is removed by filtration and the hydrochloridesalt of the product of formula (VIII) is precipitated by addition of anonsolvent, for example, ethyl ether, benzene or hexane. Alternatively,the free base of formula (VIII) may be isolated by evaporating thefiltrate from the debenzylation to dryness, partitioning the residuebetween aqueous alkali, for example sodium hydroxide, and a solvent suchas chloroform on ethyl ether. The free base is then isolated by standardmethods such as those described above.

The free bases of formula (VIII) may also serve as precursors for thenovel compounds of formula (II) as illustrated by the following reactionsequence wherein X₁, Y₁, Z₁ and n are as previously defined. ##STR15##The acylation of the compounds (VIII) to form the intermediates offormula (X) may employ the acids of formula (IX) or the correspondingacid chlorides or acid bromides. When the acids of formula (IX) areemployed in the acylation, approximately equimolar amounts of said acidand compound of formula (VIII) are contacted in the presence of areaction-inert organic solvent and certain condensing agents known inthe art for forming peptide bonds. Such agents include carbodiimides,for example, dicyclohexylcarbodiimide and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, andalkoxyacetylenes, for example, methoxyacetylene and ethoxyacetylene. Thepreferred condensing agent is dicyclohexylcarbodiimide. Examples of saidsolvents which may be employed are dichloromethane, chloroform,tetrahydrofuran, ethyl ether and benzene. While the reaction may becarried out at a temperature of from about -10° to 50° C. withsatisfactory results, it is preferred to employ a temperature of fromabout 0° to 30° C. At this temperature the reaction is ordinarilycomplete in a few hours. The product of formula (X) is isolated, forexample, by filtering to remove insoluble material and evaporation ofsolvent. The resulting product is ordinarily of sufficient purity foruse in the next step.

The intermediate of formula (X) is then reduced with lithium aluminumhydride to obtain the desired compound of formula (II). The reduction ispreferably carried out in the presence of an inert gas such as nitrogenor argon and under substantially anhydrous conditions. From about 2 to10 molar excess of lithium aluminum hydride is suspended in an etherealsolvent, for example, ethyl ether or tetrahydrofuran and the mixture ispreferably cooled to a temperature of about 0° to 10° C. Theintermediate of formula (X), obtained as described above, is ordinarilydissolved in the same solvent and the solution added dropwise. Theresulting mixture is then reacted, ordinarily at or about roomtemperature for a period of from about 0.5 to 4 hours to attainsubstantial completion of the reaction. The excess lithium aluminumhydride is then decomposed, e.g., by cautious addition of water, theresulting mixture filtered and the filtrate evaporated to dryness toprovide the desired product of formula (II) which may be furtherpurified, if desired, by standard methods known to one skilled in theart. Alternatively, the free base, (II), may be converted to a salt suchas, for example, the hydrochloride addition salt by addition ofanhydrous hydrogen chloride to a solution of the base in a solvent suchas ethanol, ethyl ether or mixtures thereof. The precipitated salt maythen be collected, e.g., by filtration. The products (II) may be furtherpurified, if desired, for example, by column chromatography on silicagel.

An alternate method for providing the 4a,9b-trans-compounds of formula(II) in admixture with the corresponding dehydrated compounds of formula(III) is illustrated as follows: ##STR16## In which X₁, Y₁, Z₁ and n areas previously defined and m is 2 or 3. The reaction with borane in ethersolvent, preferably in tetrahydrofuran, and subsequent treatment withacid, is carried out under the conditions described above forpreparation of the 2-benzyl compounds of formula (VII). The products(II) and (III) are separated, for example by column chromatography onsilica gel.

The relative amounts of products (II) and (III) will vary depending uponthe amount of acid, for example, hydrochloric acid, and the time ofheating at reflux after the reduction with BH₃.THF has taken place.Higher amounts of acid and longer reflux times favor the dehydratedproduct of formula (III); while lower amounts of acid and shorter refluxperiods favor the formation of the product (II).

The compounds of formula (II) or (III) may also serve as precursors ofthe free bases of formula (VIII). This is carried out employing, forexample, ethyl chloroformate followed by alkaline hydrolysis asdescribed above for the debenzylation of the compounds of formula (VII)wherein R₂ is benzyl, to obtain the free bases of formula (VIII).

Oxidation of the compounds of formula (II) employing reagents andconditions which are known to selectively convert secondary alcohols tothe corresponding ketones, provides the novel products of formula##STR17## wherein X₁, Y₁, Z₁ and n are as previously defined. Examplesof such oxidizing agents which may be employed in this reaction arepotassium permanganate, potassium dichromate and chromium trioxide andthe preferred reagent is chromium trioxide in the presence of pyridine.In carrying out this reaction with the preferred reagent, the startingalcohol of formula (VI) in a reaction-inert solvent, for example,dichloromethane, chloroform or benzene, is added to a mixture containingup to a ten molar excess of chromium trioxide and a similarly largemolar excess of pyridine and the mixture stirred, ordinarily at roomtemperature, until the reaction is substantially complete. Ordinarily,from about 15 minutes to one hour will suffice. The product is isolated,for example, by removal of insoluble material by filtration, extractingthe filtrate with a dilute aqueous alkali such as sodium hydroxidesolution, drying the organic layer and evaporating to dryness. Theresidual product may be further purified, if desired, for example, bycolumn chromatography.

As will be recognized by one skilled in the art, the4a,9b-trans-compounds of formula (IV) and (VIII) form a single racematewhich can be resolved into a pair of enantiomers, one of which isdextrorotatory and the other is levorotatory. The 4a,9b-trans-compoundsof formula (II), having an additional assymmetric carbon atom in the2-substituent, form two diastereomers, each of which is resolvable intodextrorotatory and levorotatory enantiomers.

It has now been found that the tranquilizing activity of the compoundsof formula (I), resides in such compounds wherein the5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole moiety (A) isdextrorotatory. The corresponding compounds wherein moiety (A) islevorotatory being of significantly lower activity. Active tranquilizingagents included within the scope of the invention, therefore, includethe enantiomers of formula (I) wherein said moiety (A) is dextrorotatoryas well as mixtures of enantiomers of formula (I) wherein said moiety(A) is dextrorotatory and levorotatory, including the racemic mixtures.While the nature of the 2-substituent attached to the moiety (A) to formthe compounds of formula (I) is critical for optimal tranquilizingactivity, the stereochemistry of the 2-substituent is less important.Thus, compounds of formula (II) wherein moiety (A) is dextrorotatory arehighly active when a given 2-substituent of formula (CH₂)nCHOHC₆ H₅ Z₁is racemic, dextrorotatory or levorotatory and all of these are includedwithin the scope of the invention.

The compounds of formula (II) as ordinarily obtained by theabove-described methods are a mixture of diastereomers. Methods for theseparation of such mixed diastereomers include fractionalcrystallization and chromatographic methods. The separation of mixeddiastereomers of formula (II) by fractional crystallization isordinarily sufficient to afford each of the diastereomers in a highlypurified form. Of course, column chromatography may be employed tofurther purify the diastereomers. Solvent systems useful for thefractional crystallization of the above diastereomers include, forexample, mixed solvent systems containing both a polar and non-polarsolvent. Examples of such polar solvents include ethyl acetate,methanol, ethanol, acetone and acetonitrile. Examples of such non-polarsolvents are hexane and its close homologs, benzene, toluene and carbontetrachloride. A preferred mixture of such solvents is ethyl acetate andhexane.

The resolution of the single diastereomers of formula (I) into the d-and l-enantiomers can be brought about by a variety of methods known inthe art for resolving racemic amines, see e.g., Fieser et. al.,"Reagents for Organic Synthesis", Wiley & Sons, Inc., New York, (1967),Vol. I, p. 977 and references cited therein. However, a particularlyuseful method for obtaining the enantiomers from the racemates offormula (I) is by esterification of a compound of formula (II) with anoptically active acid followed by separation of the diastereomericesters by fractional crystallization or by chromatography. Theenantiomeric ketones of formula (IV) are then obtained by oxidation ofthe corresponding enantiomers of formula (II). While a variety ofoptically active acids are known in the art for such use,L-phenylalanine has been found to be especially useful for resolving thediastereomers of formula (II) according to the following scheme in which(A) represents the 5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolemoiety and t-boc is t-butyl-oxycarbonyl. ##STR18##

In the first step of the resolution scheme depicted above, the singleracemic diastereomer of formula (II) is esterified witht-Boc-L-phenylalanine by methods known in the art for esterification ofsuch compounds. In a particularly preferred procedure, the diastereomer(II) is contacted with at least an equimolar amount oft-Boc-L-phenylalanine in the presence of a reaction inert solvent and acondensing agent at low temperature, preferably at about 0°[ to roomtemperature. Examples of suitable reaction inert solvents includechloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran andethyl ether. Preferred as solvent is chloroform and a preferredcondensing agent is dicyclohexylcarbodiimide. The reaction is ordinarilycomplete within a few hours. The resulting ester of formula (XVI) isrecovered by well known methods and reacted in the cold, preferably at-10° to 20°[C. with a molar excess of trifluoroacetic acid to remove thet-butyloxycarbonyl protecting group to provide the amino ester offormula (XVII) as a mixture of diastereomers. This mixture is thenseparated by frictional crystallization or chromatography to provide thesingle diastereomers of formula (XVII). A particularly convenient methodfor such separation is by column chromatography on silica gel. Theisolated single diastereomers are then hydrolyzed in the presence ofacid or base by well known methods to provide the separateddextrorotatory and levorotatory enantiomers of formula (II). The latterenantiomers may then be oxidized, for example, by means of chromic acidas described herein, to provide the corresponding enantiomers of formula(IV).

An alternate method for providing the enantiomeric compounds of formula(II) is by stereospecific synthesis in which the resolved enantiomers ofa tricyclic secondary amine of formula (VIII) are condensed with anenantiomeric precursor of the 2-position substituent. In order to effectstereospecific synthesis of the compounds of formula (II), a novelprocess which conveniently achieves this goal to provide optically purecompounds in high yield employing resolved reactants is outlined below.Of course, this process is also useful for providing racemic productswhen racemic reactants are employed. ##STR19## In the above reactionscheme, X₁, Y₁, Z₁ and n are as previously defined and q is 1 or 2.

The optical isomers of amine (VIII) are obtained by resolution of theracemic compounds. The resolution is carried out by means of a saltformed between the amine (VIII) and optically active acid. While avariety of acids useful in the resolution of amines are known in theart, see for example, Fieser et. al. cited above, preferred acids whichafford ready separation of the amine (VIII) are the optical isomers (D-and L-) of N-carbamoylphenylalanine. The latter are obtained by reactionof the isomeric phenylalanines with sodium cyanate by methods known toone skilled in the art. The resolution is achieved by reacting one ofthe isomeric N-carbamoylphenylalanines, for example the L-isomer, with aracemic compound of formula (VIII) in equimolar amounts in the presenceof a suitable reaction inert solvent to form a homogeneous solution ofthe salts. Upon cooling, the salt of one of the optical isomers of(VIII) is obtained as a crystalline solid which may be further purifiedif desired. The mother liquors containing primarily the salt of theother isomer is evaporated to dryness and the salt decomposed by aqueousbase such as, for example, sodium carbonate, potassium hydroxide orcalcium carbonate and the free base extracted by means of a waterimmiscible solvent, typically ethyl acetate, dried and the solventevaporated to obtain a residue enriched in the second isomer of theamine (VIII). This residue is then taken up in a reaction inert solventand treated with an equimolar amount of the other isomer ofN-carbamoylphenylalanine, for example, the D-isomer and the solutioncooled to precipitate crystals of the N-carbamoylphenylalanine salt ofthe second isomer of formula (VIII).

Each of the salts containing a single enantiomer of the amine (VIII) isthen decomposed as described above to obtain, respectively, theessentially pure dextrorotatory and levorotatory isomers of (VIII).

Some of the racemic lactols of formula (XIV) wherein q is 2, are knownin the art, Colonge et. al., Bull. Soc. Chem. France, 2005 (1966); Chem.Abstr., 65, 18547d (1966). However, the five-membered lactols (XIV),q=1) are novel compounds. The lactols may be prepared by various routes,for example, from the known compounds of the formula (XI) or thecorresponding nitriles as shown below, wherein Z₁ and q are as definedabove. ##STR20##

The ketoacid of formula (XI) is reduced conveniently, e.g., by means ofsodium borohydride by methods known to those skilled in the art toprovide the corresponding hydroxy acids of formula (XII) (or thecorresponding nitrile if cyanoketones corresponding to (XI) areemployed, followed by hydrolysis of the hydroxynitrile to provide thehydroxy acid). The hydroxy acids are readily converted to lactones(XIII) by warming under dehydrating conditions, preferably in thepresence of a reaction inert solvent, typically ethyl acetate, and inthe presence of a catalytic amount of acid, typically p-toluenesulfonicacid. The reaction mixture is ordinarily heated at reflux for about onehour, cooled, washed with brine, dried and the lactone (XIII) isolatedby evaporation of solvent.

The lactone (XIII) is reduced by means of a metal hydride reducing agentto provide the lactol of formula (XIV). While a variety of metal hydridereducing agents may be employed with some success to provide the desiredlactols, preferred reducing agents are diisobutylaluminum hydride,sodium borohydride, lithium borohydride and the former is especiallypreferred. The reaction is carried out in the presence of a reactioninert organic solvent and a reaction inert gas such as argon ornitrogen. When the preferred diisobutylaluminum hydride is employed asreducing agent, the reaction is carried out at a temperature of fromabout -80° to -70° C. Approximately equimolar amounts of the tworeactants are employed. The reaction is ordinarily complete in a fewhours or less. The reaction mixture is quenched by addition of a loweralkanol, e.g., methanol, warmed to a temperature near room temperatureand the solvent evaporated in vacuo and the lactol isolated by standardmethods which will be known to those skilled in the art.

As mentioned above, when enantiomeric compounds of formula (II) aredesired by the reaction of amine (VIII) and lactol (XIV), resolvedreactants are required. In order to obtain resolved isomers of (XIV),the resolution of the corresponding racemic hydroxyacid precursors offormula (XII) is carried out.

The resolution of racemic hydroxyacids (XII) is carried out in a manneranalogous to that described above for the resolution of amines (VIII),e.g., by fractional crystallization of the salts employing first e.g.,d-ephedrine to precipitate one isomer of (XII); the other isomer of(XII) is then precipitated with the antipode of ephedrine and the twosalts decomposed to obtain the dextrorotatory and levorotatory isomersof (XII), each of which is converted to lactol (XIV) as described above.For the synthesis of each of the enantiomers of formula (II) equimolaramounts of the resolved reactants of formula (VIII) and (XIV) arecontacted in the presence of a reaction inert organic solvent underreductive alkylation conditions. Methods for carrying out reductivealkylation reactions have been reviewed, for example, by Emerson,Organic Reactions 4, 174 (1948) and by Rylander in "CatalyticHydrogenation Over Platinum Metals", Academic Press, New York, 1967,p.291-303. The the reaction may be effected with a wide variety ofreducing agents known to be useful for reductive alkylation of secondaryamines with aldehydes and ketones such as, for example, hydrogen in thepresence of a catalytic amount of a noble metal catalyst such asplatinum, palladium, rhodium, ruthenium or nickel; various metal hydridereducing agents such as sodium cyanoborohydride, sodium borohydride andlithium borohydride; and formic acid. Preferred reducing agents are thenoble metal catalysts and sodium cyanoborohydride. Especially preferrednoble metals are platinum and palladium and most particularly preferredis palladium for reasons of economy and efficiency in providingenantiomeric products in high yield and with a high degree of opticalpurity.

In its preferred embodiment the amine of formula (VIII) is contactedwith an equimolar amount of lactol of formula (XIV) and one of theabove-mentioned preferred reducing agents in the presence of reactioninert organic solvent at a temperature of from about -10° to 50° C. Whenthe preferred reducing agent is sodium cyanoborohydride, at least anequivalent amount is employed. When the preferred noble metal catalystsare employed, the reaction is carried out in the presence of a molarexcess of hydrogen.

As mentioned above, the noble metal catalyst is employed in a "catalyticamount", which term is well understood by those skilled in the art. Whenthe noble metal catalysts and hydrogen are employed, the reaction may becarried out at atmospheric pressure or at high pressures up to about 10atmospheres or higher with equal facility. The factor which willordinarily determine whether the reaction is carried out at atmosphericpressure or higher pressure is the scale on which reaction is carriedout. For example, when carried out on a few grams or less of reactants,atmospheric pressure is more convenient; however, on a commercial scale,use of high pressure is usually preferable.

Examples of suitable reaction inert solvents are the lower alkanols,such as methanol, ethanol, isopropanol and n butanol, ethers such asdimethoxyethane, diethyleneglycol dimethyl ether, ethyl ether andisopropyl ether, glycols such as ethylene glycol and diethylene glycol,and glycol monoethers such as α-methoxyethanol and diethyleneglycolmonomethyl ether.

While the reaction may be carried out with some success at temperaturesof from about -50° up to the reflux temperature of the solvent,preferred reaction temperature is from about -10° to 50° C. for reasonsof convenience and efficiency. At higher temperatures, racemization ofproducts and other undesired side reactions may take place to anappreciable extent. At temperatures lower than -10° C., the reactionrate is very slow. The reaction ordinarily proceeds to completion infrom about one to five hours. The products are then isolated by standardmethods and purified, if desired, for example, by crystallization orchromatography. The desired enantiomeric products are thus obtained ingood yield and are of high optical purity.

An alternative preferred product of the invention is obtained by theabove procedure using dextrorotatory amine (VIII) and racemic lactol(XIV) in the above procedure. The product obtained, of formula (II), isoptically active due to the chirality of the amine moiety (A), definedabove. It is a highly active tranquilizing agent and also serves as aneconomical intermediate for oxidation by methods described above, to theketonic products of formula (IV).

2-Benzyl-5-phenyl-1,2,3,4-tetrahydro-γ-carboline is obtained by theFischer indole synthesis employing N,N-diphenylhydrazine andN-benzyl-4-piperidone. The mono or difluoro-substituted startingtetrahydro-γ-carbolines of formula (VI) wherein at least one of X₁ or Y₁is fluoro and R₂ is benzyl, are prepared from the correspondingcompounds of formula (VI) wherein R₂ is hydrogen by reaction with abenzyl halide such as benzyl bromide, in equimolar amounts. Therequisite compounds of formula (VI, R₂ =H) are prepared as described inU.S. Pat. No. 4,001,263. The starting tetrahydro-γ-carbolines (V) aredescribed in the same reference.

Except for the novel intermediates of formulae (VIII) and (XIV)mentioned above, the other starting materials are either commerciallyavailable, their preparation is explicitly reported in the chemicalliterature or they can be prepared by methods known to those skilled inthe art. For example, the phenylhydrazines are commercially available orare synthesized by reduction of the phenyldiazonium salt as reviewed byWagner and Zook in "Synthetic Organic Chemistry", John Wiley & Sons, NewYork, N.Y., 1956, Chapter 26; the 1-substituted-4-piperidones arecommercial reagents or prepared by the method of McElvain et al., J. Am.Chem. Soc., 70 1826(1948); the requisite 3-benzoylpropionic acids and4-benzoylbutyric acids are either commerically available or prepared bymodification of the procedure of "Organic Synthesis", Coll. Vol. 2, JohnWiley & Sons, New York, N.Y., 1943, p. 81.

As has been previously mentioned, the basic compounds of the presentinvention can form acid addition salts. Said basic compounds areconverted to their acid addition salts by interaction of the base withan acid either in an aqueous or nonaqueous medium. In a similar manner,treatment of the acid addition salts with an equivalent amount of anaqueous base solution, e.g., alkali metal hydroxides, alkali metalcarbonates and alkali metal bicarbonates or with an equivalent amount ofa metal cation which forms an insoluble precipitate with the acid anion,results in the regeneration of the free base form. The bases thusregenerated may be reconverted to the same or a different acid additionsalt.

In the utilization of the chemotherapeutic activity of said salts of thecompounds of the present invention, it is preferred, of course, to usepharmaceutically acceptable salts. Although water-insolubility, hightoxicity, or lack of crystalline nature may make some particular saltspecies unsuitable or less desirable for use as such in a givenpharmaceutical application, the water insoluble or toxic salts can beconverted to the corresponding pharmaceutical acceptable bases bydecomposition of the salt as described above, or alternately, they canbe converted to any desired pharmaceutically acceptable acid additionsalt.

Examples of acids which provide pharmaceutically acceptable anions arehydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfurous,phosphoric, acetic, lactic, citric, tartaric, succinic, maleic andgluconic acids.

As previously indicated, the compounds of the present invention arereadily adapted to therapeutic use as tranquilizing agents in mammals.

The tranquilizing agents of the present invention are characterized byrelief of such schizophrenic manifestations in humans as hallucinations,hostility, suspiciousness, emotional or social withdrawal, anxiety,agitation and tension. A standard procedure of detecting and comparingtranquilizing activity of compounds in this series and for which thereis an excellent correlation with human efficacy is the antagonism ofamphetamine-induced symptoms in rat tests, as taught by A. Weissman, etal., J Pharmacol. Exp. Ther., 151, 339 (1966) and by Quinton, et al.,Nature, 200, 178, (1963).

Another method recently reported by Leyson et al., Biochem. Pharmacol.,27, 307-316 (1978), the inhibition of ³ H-spiroperidol binding todopamine receptors, correlates with the relative pharmacologicalpotencies of drugs in affecting behavior mediated by dopamine receptors.

The γ-carbolines and the pharmaceutically acceptable salts thereof,which are useful as tranquilizers, can be administered either asindividual therapeutic agents or as mixtures of therapeutic agents. Theymay be administered alone, but are generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice. For example, theycan be administered orally in the form of tablets or capsules containingsuch excipients as starch, milk sugar, or certain types of clay, etc.They can be administered in the form of elixirs or oral suspensions withthe active ingredients combined with emulsifying and/or suspendingagents. They may be injected parenterally, and for this use they, orappropriate derivatives, may be prepared in the form of sterile aqueoussolutions. Such aqueous solutions should be suitably buffered, ifnecessary, and should contain other solutes such as saline or glucose torender them isotonic.

Although the use of the present invention is directed toward thetreatment of mammals in general, the preferred subject is humans.Obviously, the physician will ultimately determine the dosage which willbe most suitable for a particular individual, and it will vary with age,weight and response of the particular patient, as well as with thenature and extent of the symptoms and the pharmacodynamiccharacteristics of the particular agent to be administered. Generally,small doses will be administered initially, with a gradual increase inthe dosage until the optimum level is determined. It will often be foundthat when the composition is administered orally, larger quantities ofthe active ingredient will be required to produce the same level asproduced by a smaller quantity administered parenterally.

Having full regard for the foregoing factors, it is considered that adaily dosage of the compounds of the instant invention in humans ofapproximately 0.1 to 100 mg., with a preferred range of 0.5 to 25 mg,will tranquilize effectively. In those individually in which thecompounds of the present invention have a prolonged effect, the dose canbe 5 to 125 mg. a week, administered in one or two divided doses. Thevalues are illustrative and there may, of course, be individual caseswhere higher or lower dose ranges are merited.

The following examples are provided solely for the purpose ofillustration and are not to be construed as limitations of theinvention, many variations of which are possible without departing fromthe spirit of scope thereof.

EXAMPLE 1dl-trans-2-benzyl-2,3,4,4a,5,9b-hexahydro-5-phenyl-1H-pyrido-[4,3-b]indoleHydrochloride

To a solution of 0.140 moles of borane in 150 ml. of tetrahydrofuranstirred at 0° C. in a three-necked round bottom flask fitted withmagnetic stirrer, thermometer, condenser and addition funnel, andmaintained under a nitrogen atmosphere, was added a solution of 23.9 g.(0.071 mole) of 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indolein 460 ml. of dry tetrahydrofuran. The addition was carried out at sucha rate as to maintain the reaction temperature below 9° C. When theaddition was completed the resulting mixture was heated to reflux andmaintained at this temperature for one hour. The solvent was thenevaporated in vacuo to afford a white solid mass which was suspended in40 ml. of dry tetrahydrofuran and heated, slowly at first, with 180 ml.of a 1:1 by volume mixture of acetic acid and 5 N hydrochloric acid. Theresulting suspension was heated at reflux for one hour, then cooled.Evaporation of tetrahydrofuran and part of the acetic acid resulted inprecipitation of a white solid which was separated by filtration andwashed with water. The solid was resuspended in tetrahydrofuran,filtered, washed with ethyl ether and air dried to afford 16.7 g. (63%)of the desired trans-isomer. M.P. 256°-260° C.

Evaporation of the mother liquor gave an additional 7.2 g. of product.

When the above procedure is repeated, but employing the appropriatelysubstituted 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole asstarting material, the following 4a,9b-trans-compounds are obtained inlike manner as their hydrochloride salts.

    ______________________________________                                         ##STR21##                                                                    X           Y          X         Y                                            ______________________________________                                        H           p-fluoro   H         o-fluoro                                     F           H          F         m-fluoro                                     F           p-fluoro   F         o-fluoro                                     ______________________________________                                    

EXAMPLE 2dl-trans-5-Phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

A suspension of 4.17 g.dl-trans-2-benzyl-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride in 150 ml. of absolute ethanol was hydrogenated at 50p.s.i. and 60°-70° C. using 1.0 g. of 10% Pd/C catalyst, over a two-hourperiod. The catalyst was removed by filtration and to the filtrate wasadded sufficient ethyl ether to precipitate the hydrochloride of thedesired product, 2.76 g. (87%), M.P. 235°-237° C.

The hydrochloride salt was converted to free base by partitioningbetween ether and dilute sodium hydroxide solution. The ether layer wasdried over sodium sulfate and evaporated to afford the title compound(97% yield), M.P. 74°-76° C.

EXAMPLE 3dl-trans-8-Fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride anddl-trans-8-Fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-3-butenyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride

In a 1000 ml. reaction vessel equipped with magnetic stirrer, droppingfunnel and maintained under a nitrogen atmosphere were placed 177 ml. of0.94 molar borane in tetrahydrofuran. The solution was cooled in an icebath and to the cold solution was added over 30 minutes a solution of 25g. (0.0555 mole) of8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,5-tetrahydropyrido[4,3-b]indolein 295 ml of tetrahydrofuran. The resulting mixture was stirred atambient temperature for 20 minutes, then heated at reflux for two hours.The reaction mixture was cooled and concentrated in vacuo to obtain aliquid residue. To this was added a mixture of 50 ml. each of aceticacid and 5 N hydrochloric acid whereupon vigorous gaas evolution tookplace. The mixture was heated at reflux for one hour, cooled to roomtemperature and filtered. The filtrate was cooled in ice and madealkalie by addition of 50% (w/w) sodium hydroxide solution. The basicmixture was extracted twice with 150 ml. portions of chloroform, thecombined organic layers dried over magnesium sulfate and evaporated todryness in vacuo to obtain a yellow foamed solid, 25 g. Silica gelthin-layer chromatography, employing a 1:1 by volume hexane/ethylacetate solvent system, revealed two products. The foamed solid waschromatographed on a column of silica gel, eluting with 1:1 by volumehexane/ethyl acetate and monitoring the fractions by TLC. The fractionscontaining only the faster moving product, i.e.8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-3-butenyl]-2,3,4,4a,5,9b-hexahydro-1N-pyrido[4,3-b]indole(a mixture of diastereomers) were evaporated to dryness taken up inacetone and converted to the hydrochloride salt by addition of anhydroushydrogen chloride in acetone, the resulting white solid was collected byfiltration and dried to obtain 1.5 g. of the 3-butenyl compound, M.P.270°-273° C.

The fractions containing only the slower moving8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolewere concentrated, taken up in ethyl ether and converted tohydrochloride salt by addition of anhydrous hydrogen chloride to obtain10.8 g. of this product, M.P. 241°-245° C., a mixture of twodiastereomers.

The proportion of the faster moving 3-butenyl compound is increased, upto 100%, by suitable increase in the acidity and period of heating atreflux in the acetic/hydrochloric acid mixture.

EXAMPLE 3A

When the procedure of Example 3 was repeated, but starting with8-fluoro-5-(o-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,5-tetrahydropyrido[4,3-b]indole,the faster moving component from silica gel chromatography wasidentified astrans-8-fluoro-5-(o-fluorophenyl)-2-[4-(p-fluorophenyl)-3-butenyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,M.P. 141°-142° C. The slower moving component was identified astrans-8-fluoro-5-(o-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,M.P. 195°-197° C. Each of the above products was a mixture ofdiastereomers.

EXAMPLE 4

Employing the appropriate compounds of formula (V) as starting materialsin the procedure of Example 3, the indicated 4a,9b-trans-products offormulae (II) and (III) were obtained and separated in each case. In theproducts of formula (III) m=n-1.

    ______________________________________                                         ##STR22##                                                                     ##STR23##                                                                    n         X                      Z                                            ______________________________________                                        3         F          p-fluoro     m-fluoro                                    3         F          p-fluoro    H                                            3         H          p-fluoro    p-methoxy                                    3         F          H           o-methoxy                                    3         H          H           p-fluoro                                     4         F          p-fluoro    p-fluoro                                     4         F          p-fluoro    p-methoxy                                    4         F          p-fluoro    H                                            4         F          H           o-fluoro                                     4         F          H           m-methoxy                                    4         H          p-fluoro    p-fluoro                                     4         H          p-fluoro    H                                            4         H          H           H                                            4         H          o-fluoro    p-fluoro                                     3         H          o-fluoro    p-fluoro                                     3         H          m-fluoro    m-fluoro                                     3         F          o-fluoro    p-methoxy                                    3         H          m-fluoro    H                                            4         F          o-fluoro    o-fluoro                                     4         F          m-fluoro    p-methoxy                                    ______________________________________                                    

EXAMPLE 5dl-trans-8-Fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

A. To a solution of 5.6 g. (12.4 mmole) ofdl-trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolein 40 ml. of toluene was added 5.3 ml. (55.7 mmole) of ethylchloroformate. The resulting mixture refluxed overnight then evaporatedto dryness to obtain a residual gum. To the gum was added 200 L ml. of a9:1 by volume mixture of ethanol/water. After the gum was dissolved, 15g. of potassium hydroxide was added and the resulting mixture refluxedovernight. The solvent was evaporated in vacuo and the residuepartitioned between water and chloroform. The organic extracts werewashed with water, dried over sodium sulfate and evaporated to dryness.The residual oil was taken up in ethyl acetate and passed through asilica gel column eluting first with ethyl acetate to remove by-productsthen eluting the desired product with 1:1 by volume ethylacetate/methanol. The fractions containing the title compound werecombined and evaporated to dryness to obtain 1.5 g. (43%) of yellow gumwhich crystallized upon standing, M.P. 115°-117° C.

B. Alternately,dl-trans-2-benzyl-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride is refluxed in the presence of excess ethyl chloroformateor the corresponding methyl, isopropyl or n-butyl chloroformate esters,then hydrolyzed and worked up by the procedure described above to obtainthe title compound.

EXAMPLE 6

Employing the appropriate starting material in each case and employingthe procedures of Example 5A or 5B, the following products are similarlyobtained:

dl-trans-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

dl-trans-8-fluoro-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

dl-trans-5-(o-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

dl-trans-5-(o-fluorophenyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

dl-trans-5-(m-fluorophenyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole,

dl-trans-5-(m-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

EXAMPLE 7dl-trans-2-(4-Hydroxy-4-phenylbutyl)-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoleHydrochloride

A. To the suspension arising from the admixture of 865 mg. (4.20 mmole)of dicyclohexylcarbodiimide and 748 mg. (4.20 mmole) of3-benzoylpropionic acid in 30 ml. of dichloromethane at 0° C. was added1.0 g. (4.0 mmole) ofdl-trans-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in 10ml. of the same solvent. The resulting mixture was stirred and allowedto warm to room temperature over 2 hours. After cooling again to 0° C.the reaction mixture was filtered, washed with dichloromethane and thefiltrates evaporated to obtain a residue ofdl-trans-2-[(3-benzoyl)propionyl]-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolewhich was used without purification in the next step.

B. The residue from above was dissolved in 50 ml. of tetrahydrofuran andheated to reflux. A filtered solution of lithium aluminum hydride in thesame solvent was added until gas evolution ceased (molar excess), andthe resulting mixture was stirred at reflux for 5-10 minutes, thencooled. Anhydrous powdered sodium sulfate, 17 g., was added followed by0.5 ml. of water. The resulting mixture was stirred at room temperaturefor 30 minutes, filtered, and the filtrate evaporated to dryness invacuo. The residue was chromatographed on a column containing 80 g. ofsilica gel, eluting with 4:1 (v/v) ethyl acetate/methanol to afford thefree base of the title compound after evaporation of solvent. The freebase was converted to the hydrochloride salt by dissolving it in ether,adding a saturated solution of anhydrous hydrogen chloride in etheruntil precipitation was complete, filtering and drying to afford 1.04g., M.P. 222°-224° C. Infrared spectrum (KBr), μ: 2.97, 3.43, 4.00(broad), 6.25, 6.68, 6.88, 7.51, 7.96, 8.18, 8.45, 9.82; Mass spectrum,M/e, 398, 292, 263, 249, 220, 207, 192 (100%); UV (methanol) λ_(max) 245(ε=0.653×10⁴), 270 (ε=0.914×10⁴).

EXAMPLE 8

Employing the appropriate starting material in each case selected fromthe free bases provided in Examples 2 and 5 and the appropriate3-benzoylpropionic acid, the following dl-trans-compounds were preparedby the procedure of Example 9. Products were isolated as thehydrochloride salts except as indicated.

    ______________________________________                                         ##STR24##                                                                    X.sub.1 Y.sub.1 Z.sub.1    M.P., °C.                                                                        Yield %                                  ______________________________________                                        F       F       H          220-223   18                                       H       H       F          239-245   39                                       H       H       CH.sub.3 O amorphous 54                                                                  solid (a)                                          F       F       CH.sub.3 O 45-48.5 (b)                                                                             31                                       ______________________________________                                         (a) Mass spectrum, M/e: 428, 411, 263 (100%), 220, 206, 204; Infrared         spectrum (KBr), μ: 2.98, 3.42, 4.07 (broad), 6.20, 6.26, 6.70, 6.88,       8.04, 8.54, 9.77, 12.05.                                                      (b) Melting point and yield data are for the free base.                  

EXAMPLE 9

Starting with the appropriate dl-trans-hexahydro-1H-pyrido[4,3-b]indoleselected from the products of Examples 2, 5 and 6 and the appropriatelysubstituted 3-benzoylpropionic or 4-benzoylbutyric acid, the followingcompounds are obtained by the method of Example 7.

    ______________________________________                                         ##STR25##                                                                    n         X.sub.1  Y.sub.1     Z.sub.1                                        ______________________________________                                        3         F        p-fluoro    m-fluoro                                       3         F        p-fluoro    o-methoxy                                      3         F        H           p-fluoro                                       3         H        p-flouro    p-methoxy                                      3         H        o-fluoro    m-methoxy                                      3         F        H           H                                              3         H        m-fluoro    H                                              3         H        H           m-fluoro                                       4         F        p-fluoro    p-fluoro                                       4         F        p-fluoro    p-methoxy                                      4         F        o-fluoro    H                                              4         F        H           H                                              4         F        H           m-methoxy                                      4         H        p-fluoro    H                                              4         H        m-fluoro    o-fluoro                                       4         H        o-fluoro    p-methoxy                                      4         H        H           o-methoxy                                      3         H        p-fluoro    p-fluoro                                       3         H        o-flouro    o-fluoro                                       3         F        m-fluoro    p-fluoro                                       3         H        m-fluoro    p-fluoro                                       ______________________________________                                    

EXAMPLE 10dl-trans-5-Phenyl-2-[3-(p-fluorobenzoyl)propyl]-3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoleHydrochloride

In a 25 ml. reaction vessel equipped with magnetic stirrer andmaintained under a nitrogen atmosphere were placed 0.828 ml. (8.0 mg.,10.3 mmole) of dry pyridine and 10 ml. of dichloromethane. To thesolution was added 517 mg. (5.17 mmole) of chromium trioxide and theresulting dark red suspension stirred for 15 minutes at roomtemperature. A solution of 359 mg. (0.862 mmole) ofdl-trans-5-phenyl-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolefree base in 5 ml. of dichloromethane was added in one portion. Thereaction mixture quickly changed to a brown suspension. This was stirredat ambient temperature for 30 minutes. The insoluble material wasremoved by filtration, washed with dichloromethane and the combinedfiltrate and washings were extracted with 20 ml. of 10% sodium hydroxidesolution. The organic layer was dried (MgSO₄) and evaporated to drynessin vacuo to afford a gum. The gum was purified by column chromatographyon silica gel, eluting with 1:1 by volume hexane/ethyl acetate. Thefractions containing the desired product were combined, evaporated to ayellow gum, the gum taken up in ethyl ether and treated with anhydroushydrogen chloride. The resulting suspension was evaporated to dryness,slurried with 3 ml. of cold dichloromethane. A colorless solid formedwhich was collected by filtration and dried to afford 20 mg. of thetitle compound, M.P. 244°-246.5° C.

EXAMPLE 11dl-trans-8-Fluoro-5-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoleHydrochloride

To a 100 ml. flask containing 20 ml. of dichloromethane and 1.76 ml.(21.9 mmole) of pyridine was added 1.09 g. of chromium trioxide and theresulting dark suspension was stirred at ambient temperature for 15minutes. Then was added in one portion a solution of 824 mg. (1.82mmole) ofdl-trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolefree base (obtained from the hydrochloride salt by making an aqueoussolution alkaline with sodium hydroxide, extracting with dichloromethaneand evaporating the extracts to dryness) in 10 ml. of dichloromethane.The resulting red-brown suspension was stirred at ambient temperaturefor one hour and worked-up by the same procedure employed in Example 10to obtain 25 mg. of the desired product, M.P. 260°-263° C.

EXAMPLE 12

Employing the appropriate starting material selected from the productsobtained in Example 7, 8 and 9 and oxidizing by the procedure of Example10 affords the following 4a,9b-trans compounds:

    ______________________________________                                         ##STR26##                                                                    n         X.sub.1   Y.sub.1     Z.sub.1                                       ______________________________________                                        3         F         p-fluoro    H                                             3         H         H           p-fluoro                                      3         H         H           p-methoxy                                     3         F         p-fluoro    p-methoxy                                     3         H         p-fluoro    p-methoxy                                     3         H         o-fluoro    m-methoxy                                     3         F         H           p-fluoro                                      3         F         H           H                                             3         H         H           H                                             3         F         p-fluoro    m-fluoro                                      3         H         m-fluoro    H                                             4         F         p-fluoro    p-fluoro                                      4         F         p-fluoro    p-methoxy                                     4         F         o-fluoro    H                                             4         F         H           H                                             4         F         H           m-methoxy                                     4         H         p-fluoro    H                                             4         H         m-fluoro    o-fluoro                                      4         H         o-fluoro    p-methoxy                                     4         H         H           o-methoxy                                     3         H         p-fluoro    p-fluoro                                      3         H         o-fluoro    o-fluoro                                      3         F         m-fluoro    p-fluoro                                      3         H         m-fluoro    p-fluoro                                      ______________________________________                                    

EXAMPLE 13 Separation of Diastereomers of dltrans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

A. Five grams of the mixture of diastereomers of dl-trans8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(pfluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride provided in Example 3 was converted to the free base bypartitioning between methylene chloride and 10% aqueous sodiumhydroxide. The organic phase was dried (Na₂ SO₄) and evaporated to afoam which was dissolved in 12.5 ml. of ethyl acetate and 45 ml. ofhexane at the boiling point of the mixture. After cooling over night,the precipitated product was collected by filtration to obtain 2.24 g.of product, M.P. 126°-129° C. This was recrystallized three times fromethyl acetate/hexane to give 1.22 g. of one diastereomer, designated asthe αβ-diastereomer, M.P. 132°-134° C. This free base was converted tothe hydrochloride salt by addition of an ethereal hydrogen chloridesolution to a solution of the free base in methanol to obtain 1.30 g.,M.P. 259°-260° C. High pressure liquid chromatography analysis indicatedthat it was ≧99% pure αβ-diastereomer.

B. The mother liquor from the first crystallization, above, wasevaporated to a gum, dissolved in ethyl ether and converted tohydrochloride salt by addition of ethereal hydrogen chloride solution.The resulting crystalline solid was recrystallized three times from amixture of acetonitrile/methanol, ultimately affording 1.03 g. of thesecond diastereomer, designated as the γδ-diastereomer, M.P. 237°-239°C.

High pressure liquid chromatography analysis of this produce showed thatit was about 95%, by weight, pure γδ-diastereomer contaminated withabout 5% of the αβ-diastereomer.

EXAMPLE 14 Resolutions of diastereomers of dl-trans-8-fluoro-5-(pfluorophenyl)-2-[4-hydroxy-4-(pfluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole A.Resolution of αβ-Diastereomer into δ-Enantiomer and β-Enantiomer

A solution of 2.40 g. (5.3 mmole) of racemic αβ-diastereomer, obtainedabove, and 2.0 g. (7.5 mmole) of N-t butoxycarbonyl-L phenylalanine in80 ml. of chloroform was cooled in the ice-bath under a nitrogenatmosphere. To the stirred solution was added 1.55 g. (7.5 mmole) ofdicyclohexylcarbodiimide and the resulting mixture was stirred for onehour at 0° C. and another hour at room temperature. The precipitatedsolid (urea) was separated by filtration and washed with methylenechloride. The filtrate and washings were evaporated in vacuo and theresidue was chromatographed on silica gel, eluting with 5:1 (by volume)methylene chloride/ethyl acetate. The fractions containing the desiredesters of N t-butoxycarbonyl-L phenylalanine were combined andevaporated in vacuo to obtain 2.5 g. of a white amorphous foam.

To this foam was added 30 ml. of anhydrous trifluoroacetic acid at 0° C.and the mixture stirred in an ice bath for 30 minutes during which timesolution occurred. The trifluoroacetic acid was removed by evaporationin vacuo on a rotary evaporator without external warming of the flask.The residual solid was dissolved in cold methylene chloride and washedwith cold 1% (w/w) aqueous sodium bicarbonate solution until neutral topH test paper. The neutral organic layer was dried (MgSO₄) and thesolvent was evaporated to obtain 1.6 g. of pale yellow gum. The gum waspurified by chromatography on 40 g. of Merck 230-400 mesh silica geleluting with 35:1 (v/v) ethyl acetate/methanol. Fractions containing theL-phenylalanine ester of the α-enantiomer and those containing theL-phenylalanine ester of β-enantiomer were separated, and evaporated todryness in vacuo to obtain 636 mg. and 474 mg., respectively.

A stirred solution of 625 mg. of the L-phenylalanine ester ofα-enantiomer in 10 ml. of methanol at room temperature was treated with10% aqueous sodium hydroxide until cloudy and was then stirred for 30minutes at room temperature. The methanol was removed by evaporationunder reduced pressure and 10 ml. of water was added. The aqueoussuspension was extracted with methylene chloride and the combinedorganic layers were dried over magnesium sulfate. Evaporation of thesolvent gave a pale yellow gum which was dissolved in acetone (5 ml.)and treated with an excess of ethereal hydrogen chloride from which thehydrochloride salt of the dextrorotatory α-enantiomer crystallized asplatelets, 380 mg., M.P. 251°-255° C. [α]_(D) ²⁰ =+32.2° (C=1.67 inmethanol).

Hydrolysis of the L-phenylalanine ester of the β-enantiomer (474 mg.obtained above) similarly provided the levorotatory β-enantiomer of8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride, M.P. 252°-255° C., [α]_(D) ²⁰ =-33.0° (C=1.67 inmethanol).

HPLC analysis showed the α-enantiomer and the β-anantiomer were each of99% or higher purity.

B. Resolution of γδ-Diastereomer into γ- and δ-Enantiomers

The γδ-diastereomer of trans-8-fluoro-5-(pfluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-[4,3-b]indolewas reacted with N-t-butoxycarbonyl-L-phenylalanine, the resultingt-boc-L-phenylalanine ester reacted with trifluoroacetic acid to removethe amino protecting (t boc) group, and the amino acid esterschromatographed to separate the L phenylalanine esters of theγ-enantiomer and the δ-enantiomer as described in Part A above. Theseparated γ- and δ-esters were then hydrolyzed separately and purifiedto obtain the dextrorotatory γ-enantiomer and the levororatoryδ-enantiomer as the hydrochloride salts by the procedure described inPart A above.

γ-enantiomer:

M.P. 240°-248° C. (dec.)

[α]_(D) ²⁰ =+3.1° (c=1.67, methanol)

δ-enantiomer:

M.P. 240°-248° C. (dec.)

[α]_(D) ²⁰ =-2.7° (c=1.67, methanol)

HPLC analysis showed that the γ-enantiomer was about 95% pure and theδ-enantiomer was of 97% purity. The lower purity of these enantiomers isexpected in view of the above-mentioned contamination of theγδ-diastereomer with αβ-diastereomer.

EXAMPLE 15 A. D(-)-N-carbamoylphenylalanine

To a suspension of 16.52 g. (0.10 mole) D(+)-phenylalanine in 75 ml. ofwater was added 12.4 g. (0.10 mole) of sodium carbonate hydrate. To theresulting solution was added, with stirring, 12.17 g. (0.15 mole) ofpotassium cyanate and the mixture was heated on the steam bath (internaltemperature 85°-90° C.) for 1.5 to 2.0 hours. After cooling in an icebath, the reaction mixture was carefully acidified to pH 1-2 withconcentrated hydrochloric acid. The precipitate was collected byfiltration, washed with ice water then with ethyl ether to obtain 15 g.of crude product. This was recrystallized by dissolving in 250 ml. ofwarm methanol, diluting with 400 ml. of water, allowing to cool slowlyto room temperature, then refrigerated until precipitation was complete.The product was obtained as white opaque needles in 58% yield afterrecrystallization, M.P. 203°-204° C. (dec.), [α]_(D) ²⁰ (-) 40.7°(methanol).

B. L(+)-N-carbamoylphenylalanine

Employing L(-)-phenylalanine in the above procedure in place of theD(+)-isomer afforded L(+)-N carbamoylphenylalanine in 42% yield afterrecrystallization, M.P. 205°-207° C. (dec.), [α]_(D) ²⁰ (+) 39.0°(methanol).

EXAMPLE 16 Resolution ofdl-trans-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoleA. Resolution of Enantiomeric N-carbamoylphenylalanine Salts

1. To one equivalent of dl-trans8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolefree base dissolved in a minimum amount of ethanol was added oneequivalent of L(+) N carbamoylphenylalanine. The mixture was heated on asteam bath while adding additional ethanol until a homogeneous solutionwas obtained. The solution was allowed to cool to room temperature andthe precipitated white needles of the L(+) N carbamoylphenylalanine saltof the (-) enantiomer of the free base were collected by filtration anddried, M.P. 207°-209° C., [α]_(D) ²⁰ -5.9° methanol.

2. The mother liquor from above was evaporated to dryness, the residuepartitioned between aqueous sodium carbonate and ethyl acetate, theorganic layer dried over magnesium sulfate and evaporated in vacuo toafford a residual oil. The oil was dissolved in a small amount ofethanol and treated with one equivalent ofD(-)-N-carbamoylphenylalanine. The mixture was warmed on the steam bathwhile adding more ethanol until solution was complete. The solution wascooled and worked up as above to afford a 92% yield of crudeD(-)-N-carbamoylphenylalanine salt of the (+) enantiomer of the freebase. This was recrystallized from ethanol (75 ml./g.) in 65% overallyield, M.P. 209°-211° C., [α]_(D) ²⁰ =+6.6° (methanol).

B. Isolation of Enanantiomeric Free Base Hydrochloride Salts

1. The enantiomeric N-carbamoylphenylalanine salt obtained in Part A, 1was partioned between aqueous saturated sodium bicarbonate and ethylacetate, the organic layer dried over magnesium sulfate and concentratedin vacuo without heating. The residual oil was dissolved in anhydrousethyl ether (50-100 ml./g.) and dry hydrogen chloride gas is passed overthe surface of the solution with swirling to afford a white precipitate.The excess hydrogen chloride and ether are removed by evaporation atreduced pressure and ambient temperature to give(-)-trans-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride in about 96% yield. This was recrystallized by dissolvingin a minimum amount of boiling ethanol, and addition of ethyl etheruntil the solution becomes turbid. The product was obtained as smallwhite crystals (75% recovery), M.P. 258°-260° C., [α]_(D) ²⁰ (-)40.9°(methanol). 2. In the same manner, (+) trans8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolewas obtained from the salt provided above in Part A,2, in 96% crudeyield and 75% recovery upon recrystallization, M.P. 260°-262.5° C.,[α]_(D) ²⁰ (+)39.2° (methanol).

EXAMPLE 17 Resolution of dl-4-hydroxy-(p-fluorophenyl)-butyric acid

A. Commercial γ-(p-fluorophenyl)-γ-butyrolactone, 18.0 g. (0.10 mole)was added to a solution of 14.0 g. (0.35 mole) of sodium hydroxide in100 ml. of water and the mixture heated at reflux for 40 minutes. Aftercooling to 0° C., 70 ml. of 6 N hydrochloric acid was added at 0°-15° C.for one hour. The white solid which formed was filtered, washed withpentane and air dried to affordracemic-4-hydroxy-4-(p-fluorophenyl)butyric acid, 18.43 g., (93% yield).When heated to temperatures of about 100 C., the hydroxy acid wasconverted back to the starting lactone.

B. The hydroxy acid obtained above, 18.43 g. (0.093 mole) was dissolvedin 200 ml. of ethyl acetate with gentle warming and to the solution wasadded a solution of 15.04 g. (0.91 mole) of d-ephedrine, [α]₅₇₈ =(+)11.4(acetone), in 80 ml. ethyl acetate. The mixture was stirred at roomtemperature over night during which time a crop of crystals formed, wasremoved by filtration and air dried to obtain 18.3 g., M.P. 97°-99° C.This material was recrystallized by dissolving it in a minimum amount ofhot ethyl acetate and allowing to stand at ambient temperature overnight. After three such recrystallizations, 8.9 g. of the d-epedrinesalt of l-4-hydroxy-4-(p-fluorophenyl)butyric acid, M.P. 105.5°-106.5°C. was obtained.

This product was taken up in a mixture of ice cold 5% hydrochloric acid(300 ml.) and ethyl acetate (150 ml.), the aqueous phase extracted fivetimes with 100 ml. portions of cold ethyl acetate, the combined organicextracts washed with saturated brine and dried (MgSO₄). The solvent wasevaporated in vacuo to a small volume to obtain 3.8 g. of the1-enantiomer as crystals, M.P. 98°-104° C., [α]₅₇₈ =(-)32.6°. Uponrecrystallization from methylene chloride, the optical rotation was[α]₅₇₈ =(-)33.4° C. An additional 0.4 g. of product was obtianed fromthe combined filtrates from the three crystallizations above.

C. The first filtrate from Part B above was evaporated to dryness invacuo to obtain 15.5 g. of residue which was taken up in a mixture ofcold 5% hydrochloric acid and ethyl acetate and the aqueous phaseextracted with fresh ethyl acetate. The combined organic layers weredried (MgSO₄) and solvent evaporated to obtain 8.19 g. (0.040 mole) ofhydroxy acid. This was taken up in fresh ethyl acetate (100 ml) and asolution of 6.60 g. (0.040 ml.) of 1-ephedrine in 50 ml. of ethylacetate was added. The mixture was stirred over night at roomtemperature and the precipitated salt recovered by filtration and airdried, 12.2 g., M.P. 101°-104° C. The salt was recrystallized four timesfrom ethyl acetate to obtain 8.2 g. of the 1-ephedrine salt ofd-4-hydroxy-4-(p-fluorophenyl))butyric acid, M.P. 105.5°-107° C. Thissalt was decomposed by treatment with ice cold 5% hydrochloric acid andethyl acetate as described in Part B above, to provide 4.0 g. of thed-hydroxy acid, M.P. 98°-104° C., [α]₅₇₈ =(+)33.1°.

EXAMPLE 18 d(+)-and l(-)-γ(p-Fluorophenyl)-γ-butyrolactone

A. l(-)-4-hydroxy-4-(p-fluorophenyl) butyric acid provided in Part B ofExample 17, (250 mg., 1.26 mmole) was dissolved in 15 ml. of ethylacetate and several crystals of p-toluenesulfonic acid was added. Themixture was heated at reflux for 25 minutes, cooled to room temperature,washed with saturated brine and dried (MgSO₄). The solvent wasevaporated to yield 216 mg. (91%) of the l-lactone as a white solid,M.P. 52°-54° C., [α]₅₇₈ =(-)4.0°.

B. d(+)-4-hydroxy-4-(p-fluorophenyl) butyric acid when treated in thesame manner afforded the d-lactone, [α]₅₇₈ =(+)4.3°.

EXAMPLE 19 5-(p-Fluorophenyl)-2-hydroxytetrahydrofuran

A. To a solution of 594 mg. (3.0 mmole) ofd(+)-4-hydroxy-4-(p-fluorophenyl) butyric acid, [α]₅₇₈ =33.1° (acetone)in 25 ml. of ethyl acetate was added 10 mg. of p-toluenesulfonic acidhydrate and the mixture heated at reflux for 30 minutes. The solvent wasevaporated in vacuo, chasing the last traces of solvent with 20 ml. oftoluene. The residual lactone was taken up in 30 ml. of fresh tolueneand cooled under a nitrogen atmosphere to -74° C. by means of a dryice/acetone bath. To this was added, dropwise over a 30 minute period,4.2 ml. (3.3 mmole) of 0.804 M diisobutylaluminum hydride (Dibal) inhexane while maintaining the mixture below -72° C. The reaction mixturewas stirred for an additional 30 minutes at -72° to -74° C., quenchedwith methanol and warmed to 0° C. The solvent was evaporated in vacuo,residue triturated four times with boiling methanol and the methanolfiltered. The combined methanol extracts were evaporated to a viscouspale yellow oil which was one spot by TLC. It was used as anintermediate without further purification.

B. Levorotatory 4-hydroxy-4-(p-fluorophenyl) butyric acid obtained abovein Example 17 and the commercially available racemic compound wereconverted, respectively, to the corresponding enantiomeric and racemictitle compounds by the procedure of Part A.

EXAMPLE 20

Starting with the appropriate d-, l-, or dl-4-hydroxy-4-arylbutyric acidor 5-hydroxy-5-arylvaleric acid, or the corresponding lactone, in theprocedure of Example 19, Part A, provides the following compounds inlike manner.

    ______________________________________                                         ##STR27##                                                                    When q is 1:         When q is 2:                                             Z.sub.1              Z.sub.1                                                  ______________________________________                                        H                    H                                                        o-F                  p-F                                                      m-F                  o-F                                                      p-OCH.sub.3          p-OCH.sub.3                                              m-OCH.sub.3          m-OCH.sub.3                                              ______________________________________                                    

The requisite 6-aryl-6-hydroxyvaleric acid lactones are prepared by themethod of Colonge, et. al., Bull. Soc. Chim. France., 2005-2011 (1966);Chem. Abstr., 65, 18547d (1966).

EXAMPLE 21 Chiral synthesis of enantiomers of8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoleα-Enantiomer

5-(p-fluorophenyl)-2-hydroxytetrahydrofuran obtained fromd(+)-4-hydroxy-4-(p-fluorophenyl) butyric acid in Example 19, Part A,230 mg., was dissolved in 30 ml. of methanol. Dextrororotary8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole free base, 404 mg. (1.25 mmole) was added, the mixture stirredfor 15 minutes, 150 mg. of 10% palladium-on-carbon catalyst was addedand the stirred mixture hydrogenated at atmospheric pressure. Whenhydrogen uptake ceased, the catalyst was removed by filtration and thesolvent evaporated in vacuo. The residue was partitioned between ethylacetate and 10% aqueous sodium hydroxide. The aqueous layer wasextracted again with ethyl acetate, the combined extracts dried (MgSO₄)and evaporated to dryness in vacuo. The residue was chromatographed on20 g. of silica gel and eluted with ethyl acetate. The fractionscontaining the desired product were combined, evaporated to dryness,taken up in ethyl ether and converted to hydrochloride salt by additionof ethereal hydrogen chloride. Yield, 144 mg., M.P. 248°-252° C.,[α]_(D) ²² =(+)30.1° (methanol). 97.5% pure by high pressure liquidchromatography analysis.

β-Enantiomer

To a solution of 53 mg. (0.95 mmole) of potassium hydroxide in 50 ml. ofmethanol under a nitrogen atmosphere was added 613 ml. (1.90 mmole) oflevorotatory8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride [α]_(D) =(-)40.9 (methanol) and the mixture stirred untilsolution was complete. To the solution was added 346 mg. (1.90 mmole) oflevorotatory 5-(p-fluorophenyl)2-hydroxytetrahydrofuran (from Example19, Part B), dissolved in a small volume of methanol and the resultingsolution stirred for 15 minutes at room temperature. The solution wascooled to 5° C. and 120 mg. (1.90 mmole) of sodium cyanoborohydride in asmall amount of methanol was added over 20 minutes. The reaction mixturewas stirred at room temperature for 45 minutes, then 250 mg. ofpotassium hydroxide was added and stirred until dissolved. The solventwas evaporated in vacuo and the residue partitioned between ethylacetate and water. After reextraction of the aqueous phase, the combinedorganic extracts were dried (MgSO₄) and evaporated in vacuo to provide1.014 g. of oil. This was chromatographed on 30 g. of silica gel asdescribed above to obtain 653 mg. of the desired product as an oil. Theoil was converted to the hydrochloride salt, as above, 400 mg., M.P.252°-257° C. (dec.), [α]_(D) ²³ =(-)33.7° (methanol) which was found tobe 99% pure β-enantiomer by HPLC. Reworking the mother liquors afforded80 mg. of a second crop, M.P. 254°-258° C. (dec.). Total yield 56%.

γ-Enantiomer

In 23 ml. of methanol were dissolved 2.07 mg. (6.4 mmole) ofd(+)-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride, [α]_(D) ²⁰ (+)39°, and 1.3 g. (7.1 mmole) of levorotatory5-(p-fluorophenyl)-2-hydroxytetrahydrofuran and the solution stirredunder a nitrogen atmosphere at room temperature for 15 minutes. Fivepercent palladium-on-carbon catalyst, 300 mg., was added and the mixturehydrogenated at atmospheric pressure for 3 hours. The reaction mixturewas worked up as described above for the α-enantiomer to obtain 2.4 g.of crude product as a yellow foam. The foam was dissolved in 40 ml. ofacetone and this was added to 20 ml. of ethyl ether saturated withhydrogen chloride. The mixture was filtered after standing at roomtemperature for two hours to obtain 980 mg. of hydrochloride salt. Thefiltrate was evaporated to provide 1.7 g. of foam. These werechromatographed separately on silica gel and the product fractionstreated again with hydrogen chloride to obtain, respectively, 140 mg.,[α]_(D) =(+)1.4° (methanol) and 800 mg., [α]_(D) =(+)1.7° (methanol).Both crops had a melting point of 254°-256° C. Each were found to be 98%pure γ-enantiomer by HPLC.

δ-Enantiomer

l(-)-8-Fluoro-5-(p-fluorophenyl)2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride, [α]_(D)=(-)40.9°, (968 mg., 3.0 mmole) and an equimolar amount ofdextrorotatory 5(p-fluorophenyl)2-hydroxytetrahydrofuran obtained by theprocedures of Example 16, Part B-1 and Example 19, Part B, were reactedby the procedure described above for the α-enantiomer to provide 1300mg. of crude δ-enantiomer as a pale yellow gum. The gum was converted tohydrochloride salt, 835 mg., (57%), M.P. 240°-250° C. This waschromatographed on 30 g. of silica gel and the eluted product fractionevaporated and again treated with ethereal hydrogen chloride to provide610 mg., M.P. 257°-260° C., [α]_(D) =(-)2.7° (methanol) which assayed98% pure by HPLC.

EXAMPLE 22

Employing the procedure of Example 16, the followingdl-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles wereeach resolved into dextrorotatory and levorotatory enantiomers andisolated as the hydrochloride salt.

    ______________________________________                                         ##STR28##                                                                            X.sub.1      Y.sub.1                                                  ______________________________________                                                H            H                                                                H            p-F                                                              H            o-F                                                              F            H                                                                F            o-F                                                              F            m-F                                                      ______________________________________                                    

EXAMPLE 23

Starting with the racemic or enantiomeric5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloridesprovided above and the d-, l- or dl-isomer of a5-aryl-2-hydroxytetrahydrofuran or 6-aryl-2-hydroxytetrahydropyran, eachof the enantiomers and diastereomers of the following formula areprepared by the procedure of Example 21.

    ______________________________________                                         ##STR29##                                                                    When n is 3:      When n is 4:                                                X.sub.1                                                                             Y.sub.1  Z.sub.1    X.sub.1                                                                             Y.sub.1                                                                              Z.sub.1                                ______________________________________                                        H     H        H          F     H      H                                      H     H        p-F        F     H      m-OCH.sub.3                            H     H        p-OCH.sub.3                                                                              H     p-F    H                                      F     p-F      m-F        H     m-F    o-F                                    F     p-F      o OCH.sub.3                                                                              H     H      o-OCH.sub.3                            F     H        p-F        H     p-F    p-F                                    H     p-F      p-OCH.sub.3                                                                              H     o-F    o-F                                    H     o-F      m-OCH.sub.3                                                                              F     p-F    p-F                                    F     H        H          F     p-F    p-OCH.sub.3                                                      F     o-F    H                                                                H     H      H                                      ______________________________________                                    

When catalytic amounts of platinum, rhodium, ruthenium or Raney nickelcatalyst are employed in place of palladium catalyst, and the reductivealkylation described in Example 21 for the α-enantiomer is carried outat temperatures of from -10° C. to 50° C. and at pressures of fromatmospheric pressure up to 10 atmospheres employing the above-mentionedlactols and 5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles, theabove compounds are obtained in a like manner.

When the reductive alkylation employing the above reactants arerepeated, but employing sodium cyanolborohydride as the reducing agentas described in Example 21 for the β-enantiomer and reactiontemperatures of from -10° C. to 50° C., the above products are similarlyobtained.

EXAMPLE 24

When each of the compounds provided in Examples 21 and 23 are oxidizedby the procedure of Example 10, the product obtained is of the followingstructure. ##STR30## When the starting alcohols of formula (I,M=CHOH)have been derived from a dextrorotatory or levorotatory5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, the aboveproducts are obtained with retention of configuration in thepyrido[4,3-b]indole moeity as evidenced by the optical rotation of theproducts. Starting alcohols of formula (l,m=CHOH), wherein, for example,the pyrido[4,3-b]indole moiety is dextrorotatory and the 2-substituentis either d-, l or dl, afford the same product.

EXAMPLE 25 A. dl-trans-8-Fluoro-5-(p-fluorophenyl)2-[4-hydroxy-4-(p-fluorophenyl(butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoleacetate

Five grams ofdl-trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride in 75 ml. of water is treated with 3 ml. of watercontaining 1.0 g. of sodium hydroxide, and the liberated free baseextracted into 150 ml. of diethyl ether. The ether layer is separated,dried over magnesium sulfate and treated with 1 ml. of glacial aceticacid. The organic solvent and excess acetic acid are removed underreduced pressure and the residue triturated with hexane and filtered.

B. Enantiomeric trans-8-Fluoro-5-(p-fluorophenyl)2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolecitrate

The hydrochlride salt of the γ-enantiomer of the title compound providedin Example 21 was converted to free base by the above procedure. Theether was evaporated and the free base taken up in ethanol. To theethanol solution was added an equimolar amount of anhydrous citric aciddissolved in ethanol and the resulting mixture stirred for 15 minutes.The solvent was removed in vacuo to provide the citrate salt.

In a similar manner pharmaceutically acceptable acid addition salts areobtained by employing hydrobromic, sulfuric, phsophoric, maleic fumaric,succinic, lactic, tartaric, gluconic, saccharic or p-toluenesulfonicacid and one of the compounds of formula (I) by the above procedures.

EXAMPLE 26 Antagonism of Amphetamine Stereotypy in Rats Test Proceduresand Results

The effects of the compounds of the present invention on prominentamphetamine-induced symptoms were studied in rats by a rating scalemodeled after the one reported by Quinton and Halliwell, and Weissman.Groups of five rats were placed in a covered plastic cage measuringapproximately 26 cm.×42 cm.×16 cm. After a brief period of acclimationin the cage, the rats in each group were treated subcutaneously (s.c.)with the test compound. They were then treated 1, 5 and 24 hrs. laterwith d-amphetamine sulfate, 5 mg./kg. intraperitoneally (i.p.). One hourafter amphetamine was given each rat was observed for the characteristicamphetamine behavior of moving around the cage. On the basis ofdose-response data after amphetamine it was possible to determine theeffective dose of the compound necessary to antagonize or block thecharacteristic amphetamine behavior of cage movement for fifty percentof the rats tested (ED₅₀). The time of rating chosen coincides with thepeak action of amphetamine which is 60-80 min. after treatment with thisagent.

Employing the above-described procedure, the following 4a,9b-transcompounds were tested for their ability to block the behavior effects ofamphetamine, the results being reported as the ED₅₀ in mg./kg. at theindicated times: ##STR31##

A. The following results were obtained on the mixture of diastereomersfor those compounds wherein R contains a secondary alcohol group and onthe single diastereomer of the other 4a, 9b-transhexahydro-pyrido-indoles.

    __________________________________________________________________________                             ED.sub.50 (mg./kg.)                                  X.sub.1                                                                             Y.sub.1                                                                            R             1 Hr.                                                                              5 Hr.                                                                              24 Hrs.                                    __________________________________________________________________________    H     H                                                                                   ##STR32##    0.032-0.1                                                                          0.032-0.1                                                                          0.1-0.32                                   H.sup.(a)                                                                           H                                                                                   ##STR33##    0.1-0.32                                                                           0.1-0.32                                                                           0.1-0.32                                   H     H                                                                                   ##STR34##    0.1-0.32                                                                           0.1-0.32                                                                           ˜1.0                                 H     H                                                                                   ##STR35##    ˜0.32                                                                        0.1-0.32                                                                           ˜0.32                                F     p-fluoro                                                                            ##STR36##    0.1-0.32                                                                           0.1-0.32                                                                           <0.32                                      F     o-fluoro                                                                            ##STR37##    <0.32                                                                              <0.32                                                                              <0.32                                      F     p-fluoro                                                                            ##STR38##    0.032-0.1                                                                          0.032-0.1                                                                          0.032-0.1                                  F     p-fluoro                                                                            ##STR39##    0.1-0.32                                                                           <0.1 <0.32                                      F     p-fluoro                                                                            ##STR40##    <1.0 <1.0 <1.0                                       H.sup.(b)                                                                           H    H             3.2-32                                                                             >3.2 >32                                        H.sup.(b)                                                                           H    C.sub.2 H.sub.5                                                                             ˜1.0                                                                         >3.2 NT.sup.(c)                                 H.sup.(b)                                                                           H    C.sub.6 H.sub.5 CH.sub.2                                                                    ˜10                                                                          3.2-32                                                                             >3.2                                       H.sup.(b)                                                                           H    C.sub.6 H.sub.5 (CH.sub.2).sub.3                                                            3.2-10                                                                             3.2-10                                                                             >10                                        Navane.sup.(d),                                                                     po                 0.32-1.0                                                                           >10  >32                                        __________________________________________________________________________     Footnotes                                                                     .sup.(a) The corresponding 4a,9bcis analog was found to have an ED.sub.50     56 mg./kg. at 1 hr.                                                           .sup.(b) U.S. Pat. No. 3,991,199.                                             .sup.(c) Not tested.                                                          .sup.(d)                                                                      cis9-[3-(4-Methyl-1-piperazinyl)propylidene]-2-(dimethylsulfonamido)thiox    nthene U.S. Pat. No. 3,310,553.                                           

B. The results of tests in which compounds of the invention reported inPart A, above are compared with the correspondingδ-substituted-5-aryl-1,2,3,4-tetrahydropyrido[4,3-b]indoles of U.S. Pat.No. 4,001,263 are summarized below. For each pair the results obtainedon the prior art compound (a) are given first and the results for thecompound of the invention (b) are given second. Where indicated the testcompound was also administered orally (p.o.) and tests were carried outfor 48 hours.

    __________________________________________________________________________                     ED.sub.50 (mg./kg.)                                          X.sub.1                                                                         Y.sub.1                                                                          R           1 Hr.  5 Hrs.                                                                             24 Hrs.                                                                            48 Hrs.                                                                            Rte. of Admin.                         __________________________________________________________________________    H H                                                                                 ##STR41##  (a) 3.2-10 (b) 0.032-0.1                                                             3.2-10 0.032-0.1                                                                   >10 0.1-0.32                                                                       -- --                                                                              i.p. i.p.                              F p-F                                                                               ##STR42##  (a) 0.1-0.32 (b) 0.032-0.1                                                           0.1-3.2 0.032-0.1                                                                  1.0-3.2 0.032-0.1                                                                  3.2-1.0 0.1-0.32                                                                   i.p. i.p.                                               (a) 1-3.2                                                                            0.32-1.0                                                                           1.0-3.2                                                                            --   p.o.                                                    (b) 0.32-1.0                                                                         0.1-0.32                                                                           0.1-0.32                                                                           --   p.o.                                   F p-F                                                                               ##STR43##  (a) 3.2-10 (b) <1.0                                                                  >10 <1.0                                                                           -- <1.0                                                                            --  --                                                                             i.p. i.p.                              F o-F                                                                               ##STR44##  (a) 0.32-1 (b) 0.1-0.32                                                              1-3.2 ca.0.1                                                                       >10 ca0.1                                                                          -- --                                                                              i.p. i.p.                                               (b) <1 <1   <1   --   p.0.                                   __________________________________________________________________________

C. Test results expressed as micrograms/kilograms, obtained on thediastereomers αβ and γδ separated in Example 13 and each of theenantiomers α, β, γ and δ resolved by the procedure of Example 14 areshown below. In each case the compounds are of the formula

    ______________________________________                                         ##STR45##                                                                                    ED.sub.50 (micrograms/kilograms)                              Compound    [α].sub.D                                                                        1 Hr.    5 Hrs. 24 Hrs.                                  ______________________________________                                        αβγδ                                                               --       32-100   32-100 32-100                                   (mixture of                                                                   diastereomers)                                                                αβ                                                                             --       --       32-100 32-100                                   α     +32.2°                                                                          120      32-100 32-100                                   β      -33.0    >1000    >1000  >1000                                    γδ                                                                            --       --       32-100 32-100                                   γ     +3.1     180      32-100 32-100                                   δ     -2.7     >1000    560    320-1000                                 ______________________________________                                    

D. ED₅₀ values (mg./kg.) obtained with purified α, β, γ and δenantiomers of the formula shown in Part C, above, but obtained bysynthesis as described in Example 21 are summarized below. The testswere carried out for 72 hours.

    ______________________________________                                        Enantiomers of                                                                Formula Shown     ED.sub.50 (mg./kg.)                                         in Part C [α].sub.D                                                                       1 Hr.  5 Hrs.                                                                              24 Hrs.                                                                             48 Hrs.                                                                             72 Hrs.                            ______________________________________                                        α   +30.1°                                                                         0.023  0.014 0.033 ca.1  >10                                β    -33.7°                                                                         >10    5.7   >10   >10   >10                                γ   +1.7°                                                                          0.178  0.045 0.018 ca.1  >1                                 δ   -2.7°                                                                          >10    5.7   >10   >10   >10                                ______________________________________                                    

EXAMPLE 27 Inhibitors of ³ H-Spiroperidol Binding to Dopamine ReceptorsTest Procedures and Results

The relative affimity of drugs for dopamine binding sites have beenshown to correlate with their relative pharmacological potencies inaffecting behavior presumably mediated by dopamine receptors, see e.g.,Burt et. al., Molecular Pharmacol., 12, 800-812 (1976) and referencescited therein. A superior binding assay for neuroleptic receptors hasbeen developed by Leyson et. al, Biochem Pharmacol, 27, 307-316 (1978)using ³ H-spiroperidol (spiperone) as the labeled ligand. The procedureused was a follows:

Rats (Sprague-Dawley CD males, 250-300 g., Charles River Laboratories,Wilmington, MA) were decapitated, and brains were immediately dissectedon an ice-cold glass plate to remove corpus striatum (˜100 mg./brain).Tissue was homogenized in 40 volumes (1 g.+40 ml.) of ice-cold 50 mM.Tris (tris[hydroxymethyl]aminomethane; (THAM).HCl buffer pH 7.7. Thehomogenate was centrifuged twice at 50,000 g. (20,000 rpm) for 10minutes with rehomogenization of the intermediate pellet in fresh THAMbuffer (same volume). The final pellet was gently resuspended in 90volumes of cold, freshly prepared (<1 week old) 50 mM Tris buffer pH 7.6containing 120 mM NaCl (7.014 g./l.), 5 Mm KCl (0.3728 g./l.), 2 mMCaCI₂ (0.222 g./l.), 1 mM MgCl₂ (0.204 g./l/), 0.1% ascorbic acid (1mg./ml.) and 10 μM pargyline (100 μl. stock/100 ml. buffer; stock=15mg./10 ml. DDW). Ascorbic acid and pargyline were added fresh daily. Thetissue suspension was placed in a 37° C. water bath for 5 minutes toinsure inactivation of tissue monoamine oxidase and then kept on iceuntil used. The incubation mixture consisted of 0.02 ml. inhibitorsolution, 1.0 ml. tissue homogenate and 0.10 ml. label (³ Hspiroperidol, New England Nuclear 23.6 Ci/mmole), prepared so as toobtain 0.5 nM in the final incubation medium (usually diluted 2.5 μl.stock→17 ml. DDW**). Tubes were incubated in sequence for 10 minutes at37° C. in groups of three, after which 0.9 ml. of each incubation tubewas filtered through Whatman GF/B filters using a high vacuum pump. Eachfilter was placed in a scintillation vial, 10 ml. of liquidscintillation fluor was added and each vial was vigorously vortexed forabout five seconds. Samples were allowed to stand over night, untilfilters were translucent, vortexed again and then counted 1.0 minute forradioactivity. Binding was calculated as fentamoles (10.sup. 15 moles)of ³ H-spiroperidol bound per mg. protein. Controls (vehicle or 1butaclamol, 10⁻⁷ M; 4.4 mg. dissolved in 200 μl. glacial acetic acid,then diluted to 2.0 ml. with DDW for 10⁻⁴ M stock solution, keptrefrigerated), blank (d-butaclamol, 10⁻⁷ M; 4.4 mg./2 ml. for 10⁻⁴ Mstock solution, same protocol as 1-butaclamol), and inhibitor solutionswere run in triplicate. The concentration reducing binding by 50% (IC₅₀)was estimated on semi-log paper. Insoluble drugs were dissolved in 50%ethanol (1% ethanol incubation).

The results obtained with the various forms of trans8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride are summarized in the table below.

    ______________________________________                                                           Inhibition of .sup.3 H-Spiroperidol                        Compound           Binding, mM IC.sub.50                                      ______________________________________                                        Mixed αβ and γδ diastereomers                                             21                                                         of Example 3                                                                  αβ-diastereomer of Example 13                                                         23                                                         Dextrorotatory α-enantiomer                                                                22                                                         of Example 14                                                                 Levorotatory β-enantiomer                                                                   1800                                                       of Example 14                                                                 γδ-diasteriomer of Example 13                                                        23                                                         Dextrorotatory γ-enantiomer                                                                25                                                         of Example 14                                                                 Levorotatory δ-enantiomers                                                                 350                                                        of Example 14                                                                 ______________________________________                                    

EXAMPLE 28 Tablets

A tablet base is prepared by blending the following ingredients in theproportion by weight indicated:

Sucrose, U.S.P.: 80.3

Tapioca starch: 13.2

Magnesium stearate: 6.5

Into this tablet base there is blended a sufficient amount of theγ-enantiomer of trans-8-fluoro-5-(pfluorophenyl)-2-[4-(p-fluorophenyl(-4-hydroxybutyl]-2,3,4,4a,5,9b-hexahydro-1Hpyrido[4,3-b] indole hydrochloride to provide tablets containing 1.0,2.5, 5.0 and 10 mg. of active ingredient per tablet. The compositionsare each compressed into tablets, each weighing 360 mg., by convenientmeans.

EXAMPLE 29 Capsules

A blend is prepared containing the following ingredients:

Calcium carbonate, U.S.P.: 17.6

Dicalcium phosphate: 18.8

Magnesium trisilicate, U.S.P.: 5.2

Lactose, U.S.P.: 5.2

Potato starch: 5.2

Magnesium stearate: 0.8

To this blend is added a second portion of magnesium stearate (0.35 g.)and sufficienttrans-5-phenyl-2-(4-hydroxy-4-phenylbutyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride to provide capsules containing 1.0, 2.5, 5.0 and 10 mg. ofactive ingredient per capsule. The compositions are filled intoconventional hard gelatin capsules in the amount of 350 mg. per capsule.

EXAMPLE 30 Suspension

A suspension ofdl-trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(methoxyphenyl)butyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido [4,3-b]indole acetae isprepared with the following composition:

Effective ingredient: g. 25.00

70% aqueous sorbitol: g. 741.29

Glycerine, U.S.P.: g. 185.35

Gum acacia (10% solution): ml. 100.00

Polyvinylpyrrolidone: g. 0.50

Distilled water, sufficient to make 1 liter.

To this suspension, various sweeteners and flavorants are added toimprove the palatabitliy of the suspension. The suspension containsapproximately 25 mg. of effective agent per milliliter.

EXAMPLE 31

Sesame oil is sterilized by heating to 120° C. for 2 hours. To this oil,a sufficient quantity of pulverized dextrorotatory α-enantiomer oftrans-8-fluoro-5-(p-fluorophenyl) 2-[4-(pfluorophenyl)-4-hydroxybutyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolehydrochloride to make 0.025% suspension by weight. The solid isthoroughly dispersed in the oil by use of a colloid mill. It is thenfiltered through a 100-250 mesh screen and poured into sterile vials andsealed.

PREPARATION A 2-Benzyl-5-phenyl-1,2,3,4-tetrahydro-γ-carboline

Crude N,N-diphenylhydrazine, 100 g. was made alkaline with aqueouspotassium hydroxide and the mixture extracted with ethyl acetate. Theorganic layer was distilled to afford 39.7 g. (0.216 mole) ofN,N-diphenylhydrazine, free base, B.P. 130°-135° C. at 1.1 mm. Hg. Thiswas dissolved in 500 ml. of absolute ethanol and 40.8 g. (0.216 mole) ofN-benzyl-4-piperidone in 500 ml. of absolute ethanol was added. Theresulting mixture was heated to 65° C. and dry hydrogen chloride gas wasadded to acidify the mixture which was then heated at reflux for fivehours. After standing overnight at room temperature the solvent wasevaporated and the residue made alkaline with sodium hydroxide solution,extracted with chloroform, the extracts dried (MgSO₄) and evaporated todryness. The residue was dissolved in ethyl ether, filtered and thefiltrate acidified with an ethereal solution of hydrogen chloride toprecipitate the crude hydrochloride salt. The salt was converted to thefree base by partitioning between aqueous sodium hydroxide and ethylacetate. The organic layers were dried, concentrated to a small volumeand chromatographed on 300 g. of silica gel eluting with 5:1hexane/ethyl acetate (by volume) to afford 12.0 g. (33%) of the desiredproduct, M.P. 150°-155° C.

PREPARATION B 8-Fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-γ-carbolineI. 8-fluoro-2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline

A mixture of 15.9 g. (0.093 mole) of N-carbethoxy-4-piperidone and 15.1g. (0.093 mole) of p-fluorophenylhydrazine hydrochloride in 150 ml. ofethanol is heated to reflux for 2 hrs. The reddish reaction mixture iscooled and filtered, and the collected solids washed with a small amountof cold 95% ethanol, 21.3 g. (88% yield), m.p. 169°-170° C. Theanalytical sample is recrystallized from ethanol-water, m.p. 169°-170°C.

Anal. Calc'd for C₁₄ H₁₅ O₂ N₂ F: C, 64.1; H, 5.8; N, 10.7. Found: C,63.8; H, 5.8; N, 10.6.

II.8-fluoro-5-(p-fluorophenyl)-2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline

To 30 ml. of N-methyl-2-pyrrolidone is added 3.45 g. (0.013 mole) of8-fluoro-2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline, 7.8 g. (0.045mole) of p-fluorobromobenzene, 4.14 g. (0.014 mole) of cuprous bromideand 1.5 g. (0.014 mole) of sodium carbonate, and the resulting mixtureheated in an oil bath at 200° C. for 6 hrs. The mixture is allowed tocool to room temperature overnight, and is then decanted into 300 ml. ofwater containing 60 ml. of ethylene diamine. Benzene (200 ml.) is addedand the two-phase system is filtered through a super-cel pad. Thefiltrate is subsequently extracted several times with a total of 700 ml.of benzene. The extracts are combined, washed succesively with water anda saturated brine solution and dried over anhydrous sodium sulfate.Removal of the solvent provides the crude product as a dark, residualoil.

The crude product in benzene is chromatographed on a silica gel columnusing 10% ethyl acetate-benzene as the eluate. Fractions 1 through 16,comprised of 10-25 ml. each, and containing p-fluorobromobenzene, arecollected and discarded. Fractions 16 to 38 are combined andconcentrated in vacuo to an oil which solidifies on standing at 5° C.overnight. The product, 3.5 g. (76% yield), is triturated with pentaneand filtered. The analytical sample is recrystallized from pentane, m.p.118°-120° C.

Anal. Calc'd for C₂₀ H₁₈ O₂ N₂ F₂ : C, 67.4; H, 5.1; N, 7.9. Found: C,67.4; H, 5.2; N, 7.8.

III. 8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-γ-carboline

A suspension of 3.56 g. (0.01 mole) of8-fluoro-5-(p-fluorophenyl)-2-carbethoxy-1,2,3,4-tetrahydro-γ-carbolineand 8.2 g. (0.146 mole) of potassium hydroxide in 53 ml. of ethanolcontaining 5 ml. of water is heated to reflux overnight. An additional3.0 g. of potassium hydroxide is added and the heating continued for 23hrs. The brownish solution is cooled, concentrated in vacuo to drynessand partitioned between water and diethyl ether. The aqueous layer isfurther extracted with ether, and the ether layers combined, washed witha saturated brine solution and dried over magnesium sulfate. Removal ofthe solvent provides the desired product as an orange solid, 2.6 g. m.p.125°-127° C. The analytical sample is recrystallized from pentane, m.p.127°-128° C.

Anal. Calc'd for C₁₇ H₁₄ N₂ F₂ : C, 71.8; H, 5.0; N, 9.9. Found: C,71.6; H, 5.1; N, 10.2.

The hydrochloride salt is prepared by bubbling hydrogen chloride into asolution of the free base in diethyl ether, m.p. 270°-272° C.

PREPARATION C2-Benzyl-8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-γ-carboline

To a stirred solution of 1.4 g. (4.9 mmoles) of8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-γ-carboline and 1.02 g.(7.4 mmoles) of potassium carbonate in 10 ml. of dimethylformamide,heated to 60° C. is added dropwise 1.01 g. (5.9 mmoles) of benzylbromide in 10 ml. of the same solvent. After heating for one hour, thereaction mixture is decanted into 200 ml. of an aqueous 2% potassiumcarbonate solution, and the resulting solution subsequently extracted(3×200 ml.) with benzene. The combined extracts are washed successivelywith water and a saturated brine solution, and dried over magnesiumsulfate. The solvent is removed in vacuo and the residual oil whichcrystallizes on standing is triturated with hexane and filtered.

PREPARATION D8-Fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydro-γ-carbolinehydrochloride

I. To a stirred suspension of 2.84 g. (0.01 mole) of8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-γ-carboline, 2.8 g. (0.01mole) of ω-chloro-p-fluorobutyrophenone, 3.15 g. (0.03 mole) of sodiumcarbonate and a trace (50 mg.) of potassium iodide in 50 ml. of4-methyl-2-pentanone gave, after heating at reflux for 15 hours followedby work-up of the reaction mixture as described in Preparation C, 2.6 g.of8-fluoro-5-(p-fluorophenyl)-2-[3-p-fluorobenzoyl)propyl]-1,2,3,4-tetrahydro-γ-carbolinefree base, M.P. 150°-155° C.

To 846 mg. (22.4 mmole) of sodium borohydride in 50 ml. of ethanol wasadded dropwise 2.5 g. (5.6 mmoles) of the γ-carboline obtained above ina warm solution of 80 ml. of ethanol and 20 ml. of tetrahydrofuran atsuch a rate that gentle reflux was maintained. After the addition wascompleted the mixture was heated at reflux for an additional hour, thencooled to room temperature. The supernatant was decanted into 300 ml. ofwater and the organic solvents removed from the aqueous phase byevaporation in vacuo. The residue was extracted with dichloromethane andthe combined extracts washed with saturated brine and over magnesiumsulfate. The solvent was evaporated in vacuo and the residue dissolvedin a mixture of ethyl ether and dichloromethane. Hydrogen chloride gaswas carefully bubbled into the solution until precipitation ceased. Thetitle compound was recovered by filtration and dried, M.P. 249°-250° C.

PREPARATION E

When 2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline or8-fluoro-2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline are reacted witho-fluorobromobenzene or m-fluorobromobenzene by the method ofPreparation B, Part II and the resulting 5-(o orm-fluorophenyl)-2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline ishydrolyzed and decarboxylated by the procedure of Part III ofPreparation B, the following compounds are obtained in like manner.

    ______________________________________                                         ##STR46##                                                                            X.sub.1     Y.sub.1                                                   ______________________________________                                                H           o-fluoro                                                          H           m-fluoro                                                          F           o-fluoro                                                          F           m-fluoro                                                  ______________________________________                                    

PREPARATION F 5-(p-Fluorophenyl)-1,2,3,4-tetrahydro-γ-carboline

Equimolar amounts of phenylhydrazine and N-carbethoxy-4-piperidone arereacted by the procedure of Preparation B, Part I, to provide2-carbethoxy-1,2,3,4-tetrahydro-γ-carboline. This is then reacted withp-fluorobromobenzene according to the procedure of Preparation B, PartII, and the product hydrolyzed by the procedure of Part III ofPreparation B to obtain the title compound.

PREPARATION G 8-Fluoro-5-phenyl-1,2,3,4-tetrahydro-γ-carboline

When p-fluororomobenzene is replaced by an equivalent amount ofbromobenzene in Part II of Preparation B and the resulting2-carbethoxy-8-fluoro-5-phenyl-1,2,3,4-tetrahydro-γ-carboline ishydrolyzed by the procedure of Part III of Preparation B, the titlecompound is similarly obtained.

PREPARATION H ##STR47##

When the product obtained in Preparation F is reacted with benzylbromide by the procedure of Preparation C, the product obtained is ofthe above formula wherein X₁ is hydrogen and Y₁ is fluoro. Similarly,when the product of Preparation G is employed as starting material inthe same procedure, a product of the above formula is obtained whereinX₁ is fluoro and Y₁ is hydrogen.

PREPARATION I

When the products of Preparation E are reacted with benzyl bromide bythe procedure of Preparation C, the following compounds are similarlyobtained.

    ______________________________________                                         ##STR48##                                                                            X.sub.1     Y.sub.1                                                   ______________________________________                                                H           o-fluoro                                                          H           m-fluoro                                                          F           o-fluoro                                                          F           m-fluoro                                                  ______________________________________                                    

PREPARATION J

Employing the appropriately substituted5-phenyl-1,2,3,4-tetrahydro-γ-carboline and Z₁ C₆ H₄ CO(CH₂)_(n) -Awhere A is Cl or Br as starting materials in each case in the procedureof Preparation D, the following compounds are similarly obtained.

    ______________________________________                                         ##STR49##                                                                    n         X.sub.1   Y.sub.1     Z.sub.1                                       ______________________________________                                        3         F         p-fluoro    m-fluoro                                      3         F         p-fluoro    H                                             3         H         p-fluoro    p-methoxy                                     3         F         H           o-methoxy                                     3         H         H           p-fluoro                                      4         F         p-fluoro    p-fluoro                                      4         F         p-fluoro    p-methoxy                                     4         F         p-fluoro    H                                             4         F         H           o-fluoro                                      4         F         H           m-methoxy                                     4         H         p-fluoro    p-fluoro                                      4         H         p-fluoro    H                                             4         H         H           H                                             4         H         o-fluoro    p-fluoro                                      3         H         o-fluoro    p-fluoro                                      3         F         o-fluoro    p-fluoro                                      3         H         m-fluoro    m-fluoro                                      3         F         o-fluoro    p-methoxy                                     3         H         m-fluoro    H                                             4         F         o-fluoro    o-fluoro                                      4         F         m-fluoro    p-methoxy                                     ______________________________________                                    

Preparation K

A mixture of 41 g. (0.25 mole) of 5-hydroxy-5-phenylvaleronitrile,obtained from 4-benzoylbutyronitrile by lithium borohydride reduction bythe procedure of Colonge et. al., Bull. Soc. Chem. France, 2005-2011(1966); Chem. Abstr., 65, 18547d (1966), and 0.30 mole of potassiumhydroxide in 200 ml. of water was heated at reflux for eight hours. Themixture was cooled to room temperature and neutralized with 10 Mhydrochloric acid, saturated with sodium chloride and extracted withether several times. The extracts were washed with water, dried (Na₂SO₄) and the ether evaporated to obtain dl-5-phenyl-5-hydroxyvalericacid lactone which was recrystallized from dilute alcohol, M.P. 62.5°C., 79% yield.

Employing the appropriate Z₁ -substituted-5-hydroxy-5-phenylvaleronitrile in the above procedure the analogouscompounds of the formula below are also prepared in like manner.

    ______________________________________                                         ##STR50##                                                                            Z.sub.1     Z.sub.1                                                   ______________________________________                                                o-F         o-OCH.sub.3                                                       m-F         m-OCH.sub.3                                                       p-F         p-OCH.sub.3                                               ______________________________________                                    

Preparation L

To 250 ml. of dry tetrahydrofuran containing 0.10 mole of sodiumborohydride is added, dropwise over 45 minutes, a solution of 41.6 g(0.20 mole) of commercial 3-(p-methoxybenzoyl)propionic acid in the samesolvent. After the addition is complete, the reaction mixture is heatedat reflux for two hours and cooled to room temperature. The excessborohydride is decomposed by addition of water then washed with water,the organic layer dried (MgSo₄) and the solvent evaporated. The residueis taken up in 500 ml. of ethyl acetate and 0.5 g. of p-toluenesulfonicacid is added. The mixture is heated at reflux for 30 minutes, cooled toroom temperature, washed with brine and dried (MgSO₄). The solvent wasevaporated to afford dl-γ-butyrolactone.

Employing the appropriate starting material in the above procedure, thefollowing racemic analogs are prepared in like manner.

    ______________________________________                                         ##STR51##                                                                    Z.sub.1                                                                       ______________________________________                                        o-OCH.sub.3                                                                   m-OCH.sub.3                                                                   o-F                                                                           m-F                                                                           ______________________________________                                    

What is claimed is:
 1. A2-Substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolecompound of the formula ##STR52## and the pharmaceutically acceptableacid addition salts thereof wherein the hydrogens attached to the carbonatoms in the 4a and 9b positions are in a trans-relationship to eachother and the 5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolemoiety is dextrorotatory; X₁ and Y₁ are the same or different and areeach hydrogen or fluoro; Z₁ is hydrogen, fluoro or methoxy; M is C=O andn is 3 or
 4. 2. A compound according to claim 1 wherein n is
 3. 3. Thecompound according to claim 2 wherein X₁ and Y₁ are each hydrogen and Z₁is p-fluoro.
 4. The compound according to claim 2 wherein X₁ is fluoroand Y₁ and Z₁ are each p-fluoro.
 5. A method for the treatment ofschizophrenic manifestations in a mammal which comprises orally orparenterally administering to a mammal in need of such treatment atranquilizing amount of a2-substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole ofthe formula ##STR53## and the pharmaceutically acceptable acid additionsalts thereof wherein the hydrogens attached to the carbon atoms in the4a and 9b positions are in a trans-relationship to each other and the5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido [4,3-b]indole moiety isdextrorotatory, X₁ and Y₁ are the same or different and are eachhydrogen or fluoro; Z₁ is hydrogen, fluoro or methoxy; M is C=O; and nis 3 or
 4. 6. The method according to claim 5 wherein n is
 3. 7. Themethod according to claim 6 wherein X₁ and Y₁ are each hydrogen and Z₁is p-fluoro.
 8. The method according to claim 6 wherein X₁ is fluoro andY₁ and Z₁ are each p-fluoro.
 9. A pharmaceutical composition active as atranquilizing agent comprising a pharmaceutically acceptable carrier anda tranquilizing amount of a compound of claim 1.